ウイルス感染症と宿主代謝‐相互作用を管理できるか?

Virus Infections and Host Metabolism—Can We Manage the Interactions?

要約

When viruses infect cells, they almost invariably cause metabolic changes in the infected cell as well as in several host cell types that react to the infection.
ウイルスが細胞に感染すると、感染細胞や、体内の感染に反応する複数の細胞型に一定の代謝変化を起こす

Such metabolic changes provide potential targets for therapeutic approaches that could reduce the impact of infection.
そうした代謝変化は、感染影響を減弱させ得る治療アプローチの潜在的な対象を提供する

Several examples are discussed in this review, which include effects on energy metabolism, glutaminolysis and fatty acid metabolism.
本総説で数例を議論し、エネルギー代謝・グルタミン分解・脂肪酸代謝への影響を対象とする

The response of the immune system also involves metabolic changes and manipulating these may change the outcome of infection.
免疫反応もまた代謝変化やその操作に関与し、それが感染後の転帰を変化させる可能性がある

This could include changing the status of herpes viruses infections from productive to latency.
これには、ヘルペスウイルスの感染状態を生産性から潜伏性へと変化させることも含まれる。

The consequences of viral infections which include coronavirus disease 2019 (COVID-19), may also differ in patients with metabolic problems, such as diabetes mellitus (DM), obesity, and endocrine diseases.
COVID-19含むウイルス感染症の転帰も、糖尿病や肥満、内分泌疾患の患者によって異なる可能性がある。

Nutrition status may also affect the pattern of events following viral infection and examples that impact on the pattern of human and experimental animal viral diseases and the mechanisms involved are discussed.
(宿主の)栄養状態もウイルス感染後に発生する事象のパターンに影響する可能性があり、ヒトや実験動物のウイルス疾患のパターンに響く事例とそのメカニズムを議論する。

Finally, we discuss the so far few published reports that have manipulated metabolic events in-vivo to change the outcome of virus infection.
最後に、ウイルス感染症の転帰を変化させるべく、生体内での代謝現象を操作した、数少ない報告について議論する。

The topic is expected to expand in relevance as an approach used alone or in combination with other therapies to shape the nature of virus induced diseases.
この話題は、ウイルス誘発性疾患の性質を形成する為、単独或いは他の療法との組み合わせで使用されるアプローチとして関連性を拡大することが期待される。

序章

Viruses are obligate intracellular parasites and usually cause changes and often times death to cells that support their replication.
 ウイルスとは義務的な細胞内寄生体であり、その複製を支える細胞に通常は変化を起こし、時に死に至らしめる。

In the infected host, this may manifest as disease which in some cases is the direct result of virus replication events in target cells.
被感染の宿主内では、これは疾患として表出し、中には標的細胞内でのウイルス複製事象の直接的な結果として生起する。

In other circumstances, clinical consequences of viral infection are attributed, fully or in part, to the host immune response to infected cells, or to extracellular virus (13).
或いは、感染細胞や細胞外のウイルスに対する宿主の免疫反応が、完全・部分的にウイルス感染症の臨床的転帰に寄与する場合もある[1-3]。

Whatever the means by which viruses act as pathogens, the infection results in changes in metabolism in the cells they infect and also in multiple cell types of the host that react to the infection.
ウイルスの病原体としての作用手段が何であれ、その結果として感染細胞や感染に反応する宿主の複数の細胞型にも代謝変化が生じる。

In addition, innate responses set off by viral infections, such as interferons type I and II, also act to modulate some aspects of metabolism (4).
加えて、ウイルス感染で開始されるIL-1やIL-2を例とした生得的反応もまた、代謝上の複数の側面を調整する因子として作用する[4]。

The consequences of many viral infections can differ in hosts that have abnormal metabolism such as diabetes mellitus (DM).
多くのウイルス感染症の転帰は、糖尿病などの代謝異常を抱える宿主間で異なる。

This has become an important issue in the case of coronavirus disease 2019 (COVID-19) infection where diabetics are more likely to suffer from more severe disease (5).
これはCOVID-19の症例でも重要な問題であり、この感染症でも糖尿病はより重症化する傾向にある[5]。

In addition, accumulating evidence shows that the state of nutrition can influence the outcome of a viral infection by causing changes in one or more aspect of metabolism (6).
更に、宿主の栄養状態が、ウイルス感染を機に一つ以上の代謝変化が生じることで、転帰に影響することを示すエビデンスが蓄積している[6]。

All of these observations imply that adjusting metabolic events during the course of a viral infection could represent a valuable approach to reshape the outcome of infections (78).
これらの観察の全ては、ウイルス感染中における代謝事象の是正が、感染の転帰を再形成する有用なアプローチになり得ることを暗示している[7,8]。

For example, when disease lesions result from immune-inflammatory reactions to infected tissues, changing the metabolic environment that limits the function of inflammatory cell subsets may change the reaction from being highly tissue damaging to one that acts to resolve lesions (8).
例えば、感染組織に対する免疫炎症反応による病変の場合、炎症細胞のサブセット機能を制限する代謝環境を変化させることで、激しい組織損傷反応を病変治癒反応へと変える可能性がある[8]。

In this brief review, we discuss evidence showing that manipulating metabolism can represent a useful approach to control the outcome of a virus infection.
本簡易総説では、代謝の操作がウイルス感染の転帰を制御する有益なアプローチになり得ることを示すエビデンスについて議論する。

Virus Infection Usually Imposes Metabolic Changes in Target Cells
ウイルス感染は通常、標的細胞の代謝変化を賦課する

Viruses themselves are metabolically inert and must rely on metabolic events in the cell to generate its component parts and to replicate new viral copies.
 ウイルス自体は代謝的に不活性であり、細胞の代謝事象に依存せねばならず、そうしてその組成分を生成し、新たな自身のコピーを複製する。

Oftentimes, the cell at the time of infection is in a quiescent state, but the infection acts to change the cell’s metabolic activity.
屡々、感染時点での細胞は静止状態にあるが、感染の作用により細胞の代謝活性が変化する。

There are multiple mechanisms by which a virus infection can induce metabolic changes in infected cell and these are listed in Table 1
ウイルス感染が、感染細胞の代謝変化を誘発するメカニズムには複数あり、一覧を表1に記す(表1)。

A common consequence of infection by many viruses is to induce high glucose metabolism (causing aerobic glycolysis, the so-called Warburg effect) in cells and to change the nature of lipid metabolism usually from fatty acid oxidation (FAO) to fatty acid synthesis (FAS) (1622).
多くのウイルス感染に共通する転帰は、細胞の高い糖代謝(好気性解糖:ワールブルグ効果)の誘発や、脂質代謝の性質の変化であり、通常は脂肪酸酸化(FAO)から脂肪酸新生(FAS)となる[16,22]。

Increased FAS is particularly necessary for those viruses that are enveloped.
FASの増加は、エンベロープを有するウイルスに特に不可欠である。

With some viruses, infection only occurs in cells that are already metabolically active with the infection often serving to downregulate one or more metabolic events.
ウイルスの中には、既に代謝的に活性状態の細胞にのみ感染が起こり、屡々感染に乗じて1つ以上の代謝事象が抑制されることがある。

This state of affairs occurs with HIV, which preferentially infects cells that are in an activated metabolic state (23).
この状態はHIV感染で生じ、この場合は代謝的に活性状態の細胞に優先的に感染する[23]。

Accordingly, HIV infects T cells undergoing the highest levels of metabolic activity, which includes elevated aerobic glycolysis (24), TCA (tricarboxylic acid cycle) cycle activity, oxidative phosphorylation (OXPHOS), and glutaminolysis (2528).
従って、HIVは代謝活性レベルが最も高い状態のT細胞に感染し、好気性解糖系[24]、TCAサイクル活動、酸化的リン酸化、グルタミン分解[25-28]の上昇などがある。

The result is cell destruction and the onset of immunosuppression.
その結果、細胞が破壊され、免疫抑制が生じる。

The multiple metabolic events that can be set into play by different types of virus infection are discussed in detail in an excellent recent review by Eisenreich et al. (29).
様々なウイルス感染の形式で生じうる複数の代謝事象がEisenreichらの素晴らしい総説で詳細に議論されている[29]。

Curiously, a wide range of mechanisms are known whereby viruses influence metabolic events in their target cells.
興味深いことに、ウイルスの標的細胞内での代謝事象への影響に関して広範なメカニズムが知られている。

Of particular interest is the variable events that occur following infection with different flaviviruses.
その内特に関心が向けられるのは、様々なフラビウイルスの感染後に生じる事象に多様性があることである。

With dengue virus infection, for example, the virus taps into the host cell’s lipid reserves which are held in lipid droplets.
例えばデングウイルス感染では、ウイルスは宿主細胞内で脂肪滴の形で保存される貯蔵脂肪に着手する。

The droplets are broken down by an autophagy type mechanism releasing fatty acids.
脂肪滴はオートファジー型のメカニズムによって破壊され、脂肪酸を放出する。

These undergo oxidation which fuels the TCA cycle providing ATP and TCA intermediates needed for viral replication (30).
これらは酸化されてTCAサイクルの燃料となり、ウイルス複製に必要なATPとTCA中間体を提供する[30]。

The Dengue related virus Zika (ZIKV) employs an interesting metabolic manipulation, although only when it infects neuronal cells, an important event in ZIKV pathogenesis that does not occur in Dengue.
デング関連のウイルスであるジカ熱は興味深い代謝操作を行うが、神経細胞への感染時のみに生じ、これはデングでは生じないジカ熱の病原性における重要な事象である。

Whereas in all cell types, ZIKV virus enhances the expression of proteins, such as the cell death proteins ZBP1, RIPK 1 and 3, in neuronal cells an additional event also occurs.
全ての細胞型においてジカ熱ウイルスは、ZBP1、RIPK1、RIPK3等の細胞死タンパク質の発現を増強するが、神経細胞においては別の事象が発生する。

Thus ZIKV infected neuronal cells express immune responsive gene 1 (IRG1) whose product generates itaconate from cis-aconite, a component of the TCA cycle (31).
そうして、ジカ熱に感染した神経細胞は免疫応答遺伝子1(IRG1)を発現し、その産物は、TCAサイクルの構成要素であるシスアアコナイトからイタコン酸を生成する[31]。

The itaconate in turn competitively inhibits succinate dehydrogenase (SDH) thus maintaining succinate levels and this keeps neuronal cells alive (3134).
イタコン酸は今度はコハク酸デヒドロゲナーゼ(SDH)を競合的に抑制し、コハク酸濃度を保つことで、神経細胞の生存を維持する[31-34]。

In addition, the inhibition of SDH activity inhibits ZIKV replication (31).
更に、SDH活性の抑制は、ジカ熱ウイルスの複製を抑制する[31]。

Why the IRG1 mediated effect only occurs in neuronal cells is unclear, but could be related to the increased resistance of mature neuronal cells to apoptosis.
IRG1を介在した作用が神経細胞にのみ生じる理由は不明だが、成熟神経細胞のアポトーシスへの抵抗性の増加に関連していると思われる。

This effect is thought to occur because neurons have some protein expression differences.
この作用は、神経細胞には幾つかタンパク質発現の違いがある為だと考えられている。

These includes low level of apoptotic protease activating factor 1, increased X-linked inhibitor of apoptosis protein associated factor, and reduced caspase-3 involved in programmed cell death (35).
そこには、低濃度のアポトーシスプロテアーゼ活性化因子1、X連鎖性アポトーシスタンパク抑制関連因子の増加、プログラム細胞死に関与するカスパーゼ3の減少がある[35]。

Hepatitis C virus (HCV) is another human pathogen that causes metabolic effects but these change at different times after infection.
C型肝炎ウイルスは代謝への影響を生起するヒト病原体だが、この作用は感染後の時間によって変化する。

In the first 24 h after infection, almost all pathways used to produce the macromolecules needed for the synthesis of new viruses are elevated (36).
感染後初期の24時間では、新たなウイルス新生に必須の巨大分子の産生の為、ほぼ全ての代謝経路が上昇する[36]。

These include both FAS and FAO with the simultaneous elevation of both FAO and FAS likely needed to provide intermediates for the TCA cycle required for virus envelop formation.
ここにはFASとFAOが含まれ、同時に上昇し、どちらもTCAサイクルの中間体の生成に必要とされ、これはウイルスのエンベロープ形成に使用される。

In later stages (48 h), several pathways are suppressed and then the infected cell’s integrity is sustained by metabolizing host cell amino acids, especially glutamine, to sustain the TCA cycle and avoid cell death (36).
感染後期(48h)では複数の経路が抑制され、宿主細胞のアミノ酸、特にグルタミンを代謝してTCAサイクルを維持し、細胞死を回避することで感染細胞の完全性を維持する[36]。

Viruses may show marked differences in the metabolic changes they impose on target cells.
ウイルスは、(種によって)標的細胞に課す代謝変化に顕著な違いを示すかもしれない。

For example, the two herpesviruses human cytomegalovirus (HCMV) and herpes simplex virus (HSV) induce quite different effects on cellular metabolism.
例えば、ヘルペスウイルスであるヒトサイトメガロウイルス(HCMV)と単純ヘルペスウイルス(HSV)は、細胞代謝に全く異なる影響を誘発する。

Infection with HCMV increases glycolytic flux, lactate excretion, FAS, and profoundly increases the level of intermediary molecules involved in the TCA cycle (37).
HCMV感染では、解糖系回転率、乳酸排泄、FASが増加し、TCAサイクルに関与する中間分子濃度が大幅に増加する[37]。

The latter are needed so that the virus can make new viral envelopes, which with HCMV are always produced de novo (10).
後者は、新生したウイルスのエンベロープ形成に利用され、これはHCMV感染では常にDe novo合成される[10]。

In contrast, infection with HSV, which replicates more rapidly (24 h) than HCMV (96 h), causes minimal effects on glycolysis and FAS but nucleotide synthesis is markedly affected with the process commandeered by HSV to produce new viral genomes (37).
反面、HSVは、複製時間がHCMV(96h)より急速(24h)であり、それにより解糖系とFASに及ぼす影響は最小限に留まるが、ヌクレオチド新生に顕著な影響があり、HSV支配下でこのプロセスはウイルスのゲノム新生に利用される[37]。

With HSV, this occurs by the virus directing the pentose pathway as well as the TCA cycle to produce the purines and pyrimidines needed to construct viral genomes (37).
HSV感染では、ウイルスがペントース経路とTCAサイクルを制御し、ウイルスゲノムの構築に必要なプリンとピリミジンを生成して発生する[37]。

Compared to HCMV, HSV relies less on FAS since its envelope is mainly made from preexisting cellular envelope material.
HCMVに比較して、HSVはFASに低依存であり、これはそのエンベロープが主に既存の細胞膜成分で構成される為である。

All herpesviruses employ two lifestyles when interacting with the host.
全てのヘルペスウイルスは、宿主との相互作用の際に、二つの生活様式を採用している。

These are productive infection, which generates new virions and oftentimes results in the infected cell being destroyed.
これらは生産的な感染であり、これにより新たなビリオンを生成し、時に感染細胞の破壊をもたらす。

Herpesviruses also set up a state of latency, which permits the virus to remain indefinitely in the host representing the usual source of infection to others once viral reactivation and viral excretion occurs.
また、ヘルペスウイルスは潜伏状態を形成するが、これは周囲への感染源となる宿主内にウイルスが永遠に留まることを可能とし、ウイルスが再活性して排泄されることで生じる。

Metabolic events during the two lifestyles are certain to be different, since latency involves minimal or even no synthesis of new viral proteins and oftentimes almost minimal effects on cellular metabolism.
潜伏期間中は、新しいウイルスタンパク質の合成がほとんど行われず、細胞代謝への影響もほとんどないため、2つの生活様式における代謝事象は確実に異なるものとなる。

Productive infections, in contrast, can provoke profound changes, as already mentioned.
対照的に、生産的な感染は、前述の通り、深い変化を生起させる。

There is also gathering evidence that changes in metabolism can be a lifestyle changing event, causing a latently infected cell to reenter the productive cycle, frequently a step needed to permit viral transmission to other hosts.
また、代謝変化は生活様式を変える事象であり、潜伏感染された細胞が再度生産サイクルに入るきっかけとなり、他の宿主へウイルスが伝搬する為に屡々必要となる段階であるというエビデンスが集積しつつある。

This issue is under investigation in our laboratory.
この問題は、当研究室で調査中である。

Some also speculate that differences in the metabolism of immune cells at local sites may influence the clinical consequences when reactivation from latency does occur (38).
また、局部位での免疫細胞の代謝上の差異が、潜伏期からの再活性化が生じた場合の臨床転帰に影響するという推測もある[38]。

Such ideas have been advocated to explain why reactivation of HSV from latency is sometimes subclinical, but on other occasions results in significant tissue damage.
こうした考え方は、HSVの潜伏期からの再活性が時に不顕性であり、時には重大な組織損傷をもたらす例もある理由を説明するために提唱されている。

Could it be, for example, that the deficiency of local fuels to support glycolysis would result in changes in viral pathogenesis?
例えば、解糖系を支える局所的燃料の欠乏が、ウイルスの病原性に変化をもたらすということはあり得るだろうか?

This concept is currently being explored.
この構想は現在検討中である。

Metabolic differences between productive and latent infections have been described for other herpesviruses, some of which could account for pathogenesis changes such as contributing to neoplasia.
生産的感染と潜伏感染の代謝上の違いは、他のヘルペスウイルスでも報告されており、その一部は、腫瘍形成に寄与する等、病態の変化の説明が可能である。

With the herpes virus Epstein–Barr virus (EBV), some genes are expressed during latency that include LMP1, LMP2, and EBNA1.
ヘルペスウイルスであるエプスタイン・バーウイルス(EBV)では、潜伏期間中にLMP1、LMP2、EBNA1などの遺伝子が発現する。

These may act to change aerobic glycolysis via effects on glucose uptake and metabolism.
これらは、グルコース吸収と代謝への影響を介して、好気的解糖系を変化させるように作用する可能性がある。

This topic is comprehensively discussed in a review by Piccaluga et al (39)..
この話題は、Piccalugaらの総説で包括的に論じられている[39]。

Inhibition of fatty acid synthesis helps to control the excessive multiplication of EBV associated nasopharyngeal carcinoma.
脂肪酸合成の阻害により、EBVに関連する上咽頭がんの過剰な増殖が制御される。

Moreover, inhibition of hexokinase 2 (HK2) also provides a useful treatment modality for nasopharyngeal carcinoma (1140).
さらに、ヘキソキナーゼ2(HK2)の阻害は、上咽頭がんに対する有用な治療法にもなりうる[11,40]。

The relevance of understanding the nature of metabolic changes imposed by different virus infections is that targeted molecular therapies may be devised that can change the outcome of infection.
様々なウイルス感染で生じる代謝変化の性質を理解することは、感染の転帰を変化させる標的分子療法を提案できる可能性と関連する。

For example, inhibiting glucose metabolism in cells infected with HIV promotes viral elimination by accelerating the death of infected cells (41).
例えば、HIVに感染した細胞でグルコース代謝を阻害すると、感染細胞の死滅が加速し、ウイルスの排除が促進される[41]。

During the late stages of HIV replication FAS is elevated, which is needed for its envelope formation.
HIVの複製後期には、エンベロープ形成に必要なFASが上昇する。

Conceivably targeting lipid metabolism could also represent a means of counteracting HIV infection and this topic has been investigated (42).
脂質代謝を標的にすることで、HIV感染への対抗手段となる可能性があり、このテーマについて研究されている[42]。

It was shown that inhibition of FAS with Fasnall and C75 inhibits HIV-1 replication in-vitro, as did Fasnall knockdown with small interfering RNA (siRNA).
FasnallとC75によるFASの阻害は、FasnallのノックダウンでsiRNAが阻害されたように、in vitroでHIV-1複製を阻害することが証明された。

The outcome of such procedures in-vivo are not available.
このような処置によるin-vivoでの転帰は得られていない。

Currently, there is minimal information regarding manipulating metabolic pathways to influence the outcome of COVID-19 infection.
現在、COVID-19感染の転帰に影響する代謝経路の操作に関する情報はほとんどない。

The Effect of Interferon Induction and Metabolic Consequences on Cell Metabolism
インターフェロン誘導と代謝の結果が細胞代謝に及ぼす影響

A common outcome of many viral infection is to induce the production of one or more types of IFNs in the cells they infect.
多くのウイルス感染に共通の転帰は、感染細胞で1種類以上のIFNの産生を誘導することである。

Curiously, many of the metabolic reprogramming events imposed by virus infections on cells that were discussed previously can be reversed by the IFN response.
不思議なことに、前述したウイルス感染によって細胞に課される代謝の初期化事象の多くは、IFN応答によって逆転させることができる。

For instance, the increased energy and lipid metabolism essential for the replication of many viruses is readily reversed by IFN, with this representing one of the ways by which the IFN response acts to control virus infections (43).
例えば、多くのウイルスの複製に必須のエネルギー代謝と脂質代謝の増加は、IFNによって容易に逆転され、これはIFN応答がウイルス感染を制御するために作用する方法の1つである(43)。

Characteristically, IFNs are released and bind to nearby cells that express specific receptors.
特徴的なのは、IFNが放出されると、特定の受容体を発現する近接細胞に結合することである。

This interaction signals the cell to express multiple (>400) so-called interferon stimulated genes (ISG) whose gene products express a wide range of biological activities (4445).
この相互作用により、複数(400以上)のいわゆるインターフェロン刺激遺伝子(ISG)を発現するよう細胞へ信号を送り、その遺伝子産物は幅広い生物学的活性を発現する[44、45]。

One common effect is that the cell produces molecules that have antiviral activity.
一般的な影響の1つは、細胞が抗ウイルス活性を持つ分子を産生することである。

Other ISGs may influence cellular metabolism that in turn can affect the outcome of a virus infection.
他のISGは細胞の代謝に影響を与え、それがウイルス感染の結果に影響を与える可能性がある。

For example, a response in cells whose IFN-γ receptors are engaged is that transcription factor expression, related with steroid biosynthesis, are changed (46).
例えば、IFN-γ受容体が関与する細胞では、ステロイド生合成に関連する転写因子の発現が変化することが知られている[46]

Transcription levels of the sterol regulatory binding protein (SREGP), which acts to downregulate cholesterol biosynthesis, are suppressed and this limits the availability of lipids which are needed particularly to generate new enveloped viruses.
コレステロール生合成の抑制作用のあるステロール制御結合タンパク質(SREGP)の転写レベルが抑制され、特に新たなエンベロープウイルスの生成に必要な脂質利用が制限される。

The SREGP can also inhibit cell entry of some viruses such as HIV-1 and it also impairs intracellular virus budding through the endoplasmic and cell membranes (4748).
SREGPは、HIV-1等のウイルスの細胞侵入も阻害し、小胞体や細胞膜を介した細胞内ウイルス出芽も阻害する[47,48]。

Another ISG induced by type I IFN, that affects cellular metabolism encodes the enzyme cholesterol-25-hydroxylase (CH25H).
1型IFNで誘導される細胞代謝に影響するもう一つのISGは、コレステロール-25-ヒドロキシラーゼ(CH25H)をコードしている。

This enzyme converts cholesterol to soluble oxysterol 25-hydroxycholesterol (25HC) that in turn serves to decrease cholesterol accumulation within cells (Figure 1).
この酵素は、コレステロールを可溶性のオキシステロールである25-ヒドロキシコレステロール(25HC)へと変換し、細胞内のコレステロール蓄積を減少させる(図1)。

The overall effect is increased resistance to several viruses such as ZIKV and other flaviviruses as well as with some togaviruses (4950).
その結果、ZIKVや他のフラビウイルス、トガウイルスなどのウイルス耐性が向上する[49,50]。

The inhibitory effect is the consequence of inhibition of viral fusion needed to enter and transport within cells as well as for the formation of new virions (51).
抑制効果は、細胞内への侵入と輸送、新たなビリオン形成に必要なウイルスの融合阻害の結果である[51]。

Upon administration to animals, the molecule 25HC can also exert antiviral effects.
動物に投与すると、25HC分子は抗ウイルス作用を発揮することができる。

For example, the pups of pregnant mice given 25HC are protected from the neurological consequences of ZIKV infection (49).
例えば、25HCを投与した妊娠マウスの子供は、ZIKV感染による神経学的転帰から保護される[49]。

In addition, in humanized mice treatment with 25HC increased resistance of their T cells to HIV infection (51).
更に、ヒト化マウスにおいて、25HCを投与すると、HIV感染に対するT細胞反応の抵抗力が増加した[51]。

Finally, by in-vitro studies 25HC was shown to have antiviral effects against several viruses that include vesicular stomatitis virus (VSV) and HSV from Herpesviridae, HIV from Retroviridae, Ebola virus (EBOV) from Filoviridae, Rift Valley fever virus (RVFV) from Bunyaviridae, Russian spring-summer encephalitis virus (RSSEV) Flavirviridae, and Nipah virus within Paramyxoviridae family (51).
最後に、25HCのin vitro研究により、
・ヘルペスウイルス科
ー水疱性口内炎ウイルス(VSV)
ーHSV
・レトロウイルス科
ーHIV
・フィロウイルス科
ーエボラウイルス(EBOV)
・ブニヤウイルス
ーリフトバレーウイルス(RVFV)
・フラビウイルス
ーロシア春夏脳炎ウイルス(RSSEV)
・パラミクソウイルス科
ーニパウイルス
などに抗ウイルス効果を示すことが明らかになった[51]。

Other ISGs can also influence lipid metabolism which then acts to limit infection and/or change the inflammatory function of cells such as macrophages.
他のISGもまた、脂質代謝に影響を与え、その結果、感染を制限したり、マクロファージのような細胞の炎症機能を変化させるように作用する。

For example, monocytes exposed to IFN-α change their lipid metabolism and undergo enhanced reactive oxygen species (ROS) production, which is essential for the antiviral effector functions of macrophages (52).
例えば、IFN-αに曝された単球は脂質代謝を変化させ、活性酸素種(ROS)の産生を促進させるが、これはマクロファージの抗ウイルスエフェクター機能に不可欠である[52]。

Another critical influence on the outcome of virus infection set off by IFN-γ triggering is induction of the enzyme indoleamine 2,3 dioxygenase (IDO) (Figure 1) (53).
IFN-γによるウイルス感染の転帰に対するもう一つの重要な影響は、インドールアミン2,3ジオキシゲナーゼ(IDO)という酵素の誘導である(図1)[53]。

This effect is usually mediated by IFN-γ and occurs mainly in macrophages and dendritic cells.
この効果は通常IFN-γに介在され、主にマクロファージと樹状細胞で生じる。

The IDO enzyme converts tryptophan to kynurenine, which has several effects on immune function.

IDO酵素はトリプトファンをキヌレニンに変換し、免疫系に複数の作用をもたらす。

These include inhibitory effects on some innate immune activities and suppression of T cell proliferation and function (54).

Cells with upregulated IDO also increase their uptake of tryptophan that acts also to inhibit the effector activity of T cells (54). IDO may also have direct inhibitory effects on some viruses that include HSV (55), HCMV (56) and human parainfluenza virus type 3 (57) perhaps mediated by depriving infected cells of adequate tryptophan. Some have suggested tryptophan deprivation could also be one means by which herpes simplex virus type 2 latency is maintained and the lytic cycle suppressed (58).

IDO酵素は、トリプトファンをキヌレニンに変換し、免疫機能にいくつかの影響を与える。例えば、一部の自然免疫活動の抑制効果や、T細胞の増殖と機能の抑制などである(54)。IDOが上昇した細胞は、トリプトファンの取り込みも増加し、T細胞のエフェクター活性を阻害する作用もある(54)。IDOは、HSV (55)、HCMV (56)、ヒトパラインフルエンザウイルス3型 (57) などのウイルスに対しても、おそらく感染細胞から適切なトリプトファンを奪うことで直接阻害する効果があるのかもしれない。トリプトファンの欠乏は、単純ヘルペスウイルス2型の潜伏期間を維持し、溶解サイクルを抑制する手段の一つである可能性も示唆されている(58)。

Metabolic Diseases and the Outcome of Virus Infections

As discussed in the previous section, when most viruses infect target cells they induce changes in metabolism that are needed for the virus to be replicated. Examples includes HCMV which upregulate glycolysis in cultured cells (10) and KSHV, which upregulate glutaminolysis in microvascular endothelial cells (18). A complete list of metabolic changes caused by various viruses is given in Table 1. Accordingly, one expects that, in situations where an aspect of host metabolism is malfunctioning, because of genetic or extrinsic reasons, the outcome of a virus infection may be affected. This topic has been mainly explored with diabetes mellitus (DM), which affects sugar metabolism. There are several reports that show that immune defense mechanisms may be less effective as a consequence of diabetes so increased susceptibility to infections is to be anticipated (5961). Several innate immune activities are diminished during diabetes. These include reduced levels of the antibacterial molecule beta defensin (62), reduction in neutrophil traps (63), reduced capacity to undergo the respiratory burst (64), and to generate antimicrobial reactive radicals such as superoxide (65). In DM, reduced production of some enzymes such as elastase and myeloperoxidase also occur and monocyte phagocytosis may be compromised as well (6667). All suppressive effects observed on innate defenses during DM may be caused by hyperglycemia, but in most instances, details of molecular events involved still need to be elucidated. In the case of beta defensin production, reduced levels during diabetic hyperglycemia were attributed to the production of dicarbonyl methylglyoxal from glucose, which changes the surface charge of beta defensin and reduces its antibacterial activity (62). The effects of DM on innate immunity explains why many bacterial infections are more common during DM, but also increased susceptibility to some virus infections has been observed (68). Most reports about changed susceptibility to virus infection in DM patients involves influenza (Flu) but it has recently become evident that diabetics (both the mostly studied type II as well as type I) may experience more severe consequences of COVID-19 infection (6970). Rising evidence also shows that COVID-19 infection may worsen the signs of diabetes (71) and also the infection may cause the onset of DM (72).

During flu epidemics, diabetics may experience more clinical problems than non-diabetics as noted in several studies (7374). Thus, diabetics require more frequent hospitalization and adult diabetics suffer more severe consequences and higher mortality rates than non-diabetics (7576). However, it is far from clear as to the mechanisms which explain increased lesions, although decreased activity of one or more immune components is usually advocated (7780). Another confounding issue is defining which aspect of DM accounts for susceptibility. Several studies link suppressed immunity with hyperglycemia and others to immune problems caused by obesity, which is a common outcome particularly with insulin resistant type 2 DM. The immunological consequences of obesity as regards effects on the pattern of viral infections is further discussed in a later section.

A better understanding of how DM can cause increased susceptibility to Flu comes from studies of type 1 DM in mouse models, which do show enhanced susceptibility (81). Mice with DM may develop higher levels of virus in their lungs compared to normal mice (82). In one model, the increased susceptibility was associated with excessive levels of glucose which acted to block the function of a surface protein lectin (SP-L) on endothelial cells that normally plays a protective role against Flu. SP-L may also act on neutrophils changing many of their functions and their ability to bind to virus.

In a drug induced model of type 1 DM, diabetic mice compared to non-diabetic controls had higher numbers of infected lung epithelial cells and developed more severe lung and pancreatic damage upon infection with several subtypes of influenza A virus (H1N1, H5N1 and H7N2) (83). In addition, higher mortality levels occurred upon infection with virulent strains of H1N1 as well as with the H5N1 subtype (83). However, this study provided no mechanistic explanation for the findings.

As we write this review, we are deep into the COVID-19 pandemic which raises the issue if diabetics are prone to develop more severe consequences of infection. Several reports indicate this is happening. For instance, in a study in China, out of 52 persons admitted to the intensive care unit (ICU), 32 died and 22% of these patients were diabetics (69). In another study of 173 patients, 16.2% were diabetics and these experienced severe disease consequences (84). In a study of 1,527 patients, two-fold higher numbers of diabetics required admittance to the ICU than normal patients (85). In New York, a recent study reported that, out of 5,700 COVID-19 patients, 33.8% had a history of diabetes which compares to around 10% in the uninfected population with diabetes (86). Thus, evidence accumulates to show that susceptibility to COVID-19 infection is increased in those with diabetes, but so far a mechanistic understanding of why this occurs remains to be shown. However, conceivably one explanation might be associated with the main receptor COVID-19 uses to enter cells, the angiotensin-converting enzyme 2 (ACE2). Curiously, patients with diabetes type 2 upregulate ACE2 at least in renal tissues (8788) and expression is further increased upon treatment with ACE inhibitors (8990). It is not clear in humans if ACE2 is upregulated in lung tissue where COVID-19 replicates, but in diabetic mice ACE2 levels are increased in lung tissues compared to healthy controls (9192). The protein component of COVID-19 that binds ACE2 is the spike protein and soluble forms of ACE2 can block virus infection (9394). Finally, trials are underway to determine if ACE2 inhibitor drugs such as the commonly used drug to control high blood pressure, losartan, has any beneficial effect on the outcome of COVID-19 infection in healthy patients. Very recently, it was observed that the incidence of Flu, which uses the ACE2 receptor to mediate lung damage, was reduced in persons that used ACE2 inhibitor drugs to control their blood pressure (9597). Moreover, prolonged drug use improved the outcome of the Flu infection (95). For the expanding knowledge concerning COVID-19 and DM and management of this interaction, an excellent review was recently published (72).

Other coronaviruses associated with human disease may also be more severe in diabetics. For example, in a study in China of 135 persons that died of severe acute respiratory syndrome (SARS), 21.5% were diabetic, whereas in 385 survivors only 3.9% had diabetes (98). With Middle East respiratory syndrome (MERS) patients in the Middle East, 50.9% of those who died were diabetic, whereas in those that recovered only 22.9% were diabetics (99). In the case of MERS, experimental studies were done in diabetic and non-diabetic control mice. The diabetic animals had more extended disease, diminished innate immune responses, and also had lower T cell responses to infection (100). It is also worth mentioning that with the SARS coronavirus, which has many similarities to COVID-19, there is evidence that the infection could damage islet cells and help precipitate DM (101). Additionally, very recently COVID-19 was advocated to upregulate ACE2 receptors on pancreatic cells making them a target for COVID-19 infection (102).

In addition to coronaviruses and flu, other virus infections may have a different, usually more severe outcome in diabetic compared to non-diabetics. One example is HSV-1 infection which causes increased facial nerve damage in diabetic mice after auricular infection (103104). There is also the suggestion that being diabetic is a risk factor for developing herpes zoster caused by varicella-zoster virus (VZV) (105), perhaps explained by diminished T cell responses in DM patients.

It would be also interesting to know if the outcome of chronic virus infections such as HIV and hepatitis are more consequential in those with diabetes (106). There is surprisingly little information on that topic, but what has been more investigated is whether HIV infection or treatments used to control HIV can act as triggering factors to set off DM. For example, one study on HIV-seropositive patients treated with highly active antiretroviral therapy showed that four times more patients developed type 2 DM than occurred in the HIV-seronegative group (107). Treatment of HIV with protease inhibitor drugs can also result in developing DM, perhaps explained by the inhibitory effects of the drugs on proteins involved in glucose metabolism such as Glut-4 (108) and cellular retinoic acid–binding protein type-I (109). Additionally, protease inhibitors may hamper pancreatic beta cell function (110) and also reduce insulin secretion (111). However, it seems that the issue of whether diabetics are more prone to develop chronic viral infections requires more research.

Obesity can also be considered as a metabolic disease and evidence accumulates to show that the outcome of a virus infection can differ in obese compared to non-obese humans and animals (112113). The topic of obesity and its influence on the outcome of virus infection has been reviewed (114). Reports document that severely obese persons may respond poorly to several vaccines and generate reduced antibody and T cell responses to infection and vaccination (115). For example, in the USA during the 2009 H1N1 pandemic, morbidly obesity patients (i.e., body mass index ≥ 40) were more prone to hospitalization and death (116) than non-obese persons. In China in the same pandemic, 19% of 9,966 patients admitted to the ICU were diabetic and many died (117). We are also realizing that obesity may predispose persons to more severe consequences of COVID-19 infection. For example, in China obese persons had a 2.42 fold higher chance of developing pneumonia upon COVID-19 infection than did the non-obese (118). Similarly, in France obese persons infected with COVID-19 had higher rates of admission to the ICU and greater needs for mechanical ventilation, outcomes directly proportional with their increased body mass indices (85). In a New York study involving 5,700 COVID-19 patients, 41.7% were obese (86). Explanations why obese persons become more susceptible to COVID-19 infection needs to be established. However, one consequence of obesity is increased expression of the ACE2 receptor on adipocytes making these cells potent targets for COVID-19, which could serve to increase the viral load (119120). Additionally, there are several changes in immune function that occur in obese subjects. These include higher ratios of M1:M2 macrophages (121), reduced T cells but elevated B cell numbers in lymph nodes (122) decreases bone marrow hematopoiesis (123) and reduced production of IFN-γ, TNF-α, IL-6, TGF-β1 by T cells (124).

Studies in mice models of obesity have revealed mechanisms that could explain their increased susceptibility to virus infection. These include effects on N-acyltransferase metabolism, fatty acid pathways (10-fold increase in 3-oxododecanoic acid and 4-hydroxyisovaleric acid) and nucleotide metabolism pathways. In obese mice, Flu can induce more oxidative stress than in lean animals and mice develop diminished T cell memory responses to infection (125).

One could anticipate that diseases of the thyroid gland, either hypothyroidism or Graves’ disease (hyperthyroidism), might be associated with changed responses to infections since thyroid hormones (TH) have a significant effect on general metabolism. For example, TH can affect liver enzymes involved in FAO and also impact on the uptake of free fatty acids by muscle and fat cells (126). Additionally, some have shown that TH can directly influence glucose utilization (127128). No reports have directly linked TH dysfunctions with changed susceptibility to a virus infection. However, some observations have tried to associate thyroid disease problems with the control of latency with some herpesviruses. One topic for evaluation has been herpes zoster, the lesion that occurs at a neurodermatome when VZV reactivates from its latent infection state (129). One study reported that when TH levels were low herpes zoster lesions were observed more frequently and showed that lesion outbreaks were less frequent in TH treated patients than in untreated persons, although differences did not reach statistical significance (130). One might also anticipate, based on mouse studies which showed that the TH receptor can influence the expression in-vitro of the latency associated transcript involved in HSV latency, that breakdown of HSV latency could be affected by TH levels, but such an effect has not been reported (131).

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Influence of Nutrition on Outcome of Virus Infections

In today’s world, many persons adjust their diet to lose or gain weight. They may also favor one form of diet over another, or use non-prescription herbal remedies. The objective is usually to improve their health and well-being, but evidence for the success of such maneuvers is less than compelling, at least when it come to the outcome of human virus infections. However, it is generally agreed that malnutrition, especially marked calorie deficiency, can increase the susceptibility of children to virus diseases such as measles and respiratory syncytial virus (132133). There is also evidence that vitamin A deficiency, which is prevalent in malnourished children in South-East Asia, results commonly in increased susceptibility to measles as well as to both respiratory and enteric viral infections. One explanation could be that several cells of the immune system particularly dendritic cells and T cells are activated and hence more protective when their promoter regions bind to the vitamin A derivative retinoic acid (134136). Other ideas include an effect of the vitamin A metabolites changing the nature of inflammatory reactions to became less tissue damaging via effects on regulatory T cells (137). In several studies, supplementation with vitamin A may increase the recovery rate and reduce mortality from measles (138139). Treated children develop both improved T cell and antibody responses (140). Vitamin A supplements are effective, but too expensive for general use in resource poor countries. However, a solution could be the use of genetically modified cereals such as golden rice that produce vitamin A precursors. This approach is resisted in most societies for non-scientific reasons.

Our most complete understanding of how nutrition can influence the outcome of virus infections comes from diet manipulation studies in animals, most commonly Flu infections in mice. Several different approaches have been used. These include comparing the outcome of a virus infection in animals or the offspring of pregnant mothers that received a so-called Mediterranean diet (~10% fat) vs. a Western (~40% fat) diet, comparing the effect of feeding diets with different fat levels and fat composition, as well as differences in fiber content (141). The consequences of nutritional changes on viral pathogenesis are often mediated by the effects of dietary intake on the composition and activity of the enteric microflora, a topic of intense interest at present. Most studies conclude that a high fat diet (HFD) can result in more severe Flu and higher mortality than occurs in recipients of a low fat diet (LFD), or normal chow diet (NCD). For example, in a study comparing responses to the pandemic Flu strain H1N1 in mice that received either a HFD, LFD, or NCD, significant differences were observed (142). Mice fed the HFD suffered 80% mortality along with enhanced lung destruction, inflammation and excess inflammatory cytokine and chemokine responses. Recipients of the LFD and NCD had mortality rates of 40 and 0% respectively. Compared to the other groups, the HFD mice showed marked changes in some metabolites in their blood. These included metabolites related to N-acyltransferase metabolism, fatty acid pathways (10-fold increase in 3-oxododecanoic acid and 4-hydroxyisovaleric acid) and nucleotide metabolism pathways. The recipients of the HFD also showed evidence of high oxidative stress, such as elevated oxidized glutathione in the lungs and the presence of high taurine levels in the urine (142). Even LFD recipients were more susceptible to influenza infection compared with mice on the NCD diet, perhaps explained by low fiber levels in the LFD (142).

The level of fat is not the only factor that affects Flu susceptibility; the chemical nature of fat in the diet also has an influence. Studies have shown that fatty acid chain length and major composition of either omega 3 or omega 6 FA (fatty acid) can also have notable effects. With regard to the latter, a diet high in omega 3 FA favors the production of anti-inflammatory activities, such as proresolving mediator synthesis (143), whereas diets rich in omega 6 FA favors proinflammatory mediator production such as prostaglandins and leukotrienes (144). Omega 3 predominance is beneficial to control inflammatory diseases that include situations where virus lesions result from a reaction dominated by inflammatory cytokine producing T cells (143). However, with viruses that cause disease by direct effects, the omega 3 rich diet may increase susceptibility. This has been noted with Flu where an omega 3 rich diet, such as feeding fish oil, results in increased severity and mortality following intranasal infection (145). The recipients developed reduced NK cell and neutrophil responses as well as reduced inflammatory mediator production involved in viral control (145). Their CD8 T cell responses were also reduced compared to animals fed the control diet.

Many studies have shown that the chain length of FAs included in the diet can play a major role in affecting the expression of inflammatory lesions caused by viruses (146147). Most studies have focused on the influence of fiber composition since high fiber diets generate an abundance of short chain fatty acids (SCFA) as a consequence of microbial digestion in the gut. However, feeding a SCFA such as butyrate as a dietary supplement can also boost the resistance of mice to Flu challenge, particularly in the early stages of infection. In one study, whereas all control mice were dead by 8 days’ post infection (PI), those fed additional butyrate showed 100, 75, and 40% survival rates at 8, 12, and 18 days’ PI respectively (147). The main effect of SCFA feeding is to expand anti-inflammatory aspects of the immune response that include Treg and M2 macrophages.

As mentioned previously, the outcome of a virus infection can be changed if animals are given a high fiber diet. This has been observed with Flu, HSV, and RSV infection all of which cause less disease when animals receive a high fiber diet (146148). The effect is now generally accepted to be explained by the expansion of bacteria such as Bifidobacteria and Bacteroides species in the gut microflora that metabolize fiber into SCFA (butyrate, acetate and propionate) (147). The resulting protective effect against flu was the consequence of an increase in the number and activation status of CD8 T cell responses and effects on the bone marrow that favored M2 macrophage differentiation, cells which produce less tissue damaging cytokines and chemokines (147). The SCFA molecules mediate such effects by binding to specific fatty acid receptors on responding cells. One consequence is an increase in mitochondrial mass and an increase in metabolites for the TCA cycle resulting enhancement of the OXPHOS energy pathway (147).

In the case of respiratory syncytial virus (RSV), protective effects were observed in mice that received a high fiber diet as well as a diet supplemented with acetate (146). In those experiments, the protective effects were attributed to the enhanced production of IFN-β from lung epithelial cells, serving to inhibit viral replication. High fiber diets may also protect against the inflammatory effects of HSV infection (148). In this instance, the protective effects were attributed to the generation of a more effective CD8 T cell response which included an expansion of memory cells to counteract future infection. Recently, our laboratory has shown beneficial effects of supplementing the diet with sodium propionate (SP) to reduce the tissue damage caused by HSV-1 infection in the eye (149).

Other studies on the effects of diet on the outcome of virus infections have evaluated the influence of supplementing the diet for certain amino acids. For example, the effect of additional glutamine and leucine has been shown to influence the outcome of vaginal infection of mice with HSV (150). Mice receiving the additional amino acids had reduced viral burdens and less mortality than those on the control diet. The supplement recipients also had elevated NK cell and IFN-γ producing CD4 Th1 T cell responses (150). Adding glutamine to the diet could also influence the stability of HSV latency. This might occur as a consequence of HSV specific CD8 T cells being expanded in the latently infected trigeminal ganglia where they are thought to function by prevented reactivation from latency (151). Another interesting observation on the value of SCFA feeding was that this could reduce the consequence of secondary bacterial infections which commonly cause Flu-associated respiratory infections to be more severe. Some have reported that a consequence of flu infection can be a change in bacterial types present in the gut, although it is not clear mechanistically how this dysbiosis occurs. The outcome is reduced presence of those bacteria species that generate SCFA especially acetate, an effect overcome by SCFA feeding (152).

Finally, with regard to nutritional influences on viral infections is the interesting observation that feeding additional glucose or SCFA can overcome the detrimental effects that high ambient temperature may exert on susceptibility to some virus infections, an issue expected to become more problematic in a warming world. Thus, when influenza infected mice were kept at 36°C compared to room temperature, they showed more susceptibility and mounted impaired immune responses that included reduced virus specific CD8 and CD4 T cells, IgG levels, and reduction in several inflammatory cytokines. The outcome of high temperature exposure was overcome either by feeding extra glucose or supplementing the diet with additional SCFA (153). Impaired immunity at high temperature has also been observed with ZIKV and Bunyavirus infections (153).

Manipulating Metabolism to Reshape the Outcome of a Virus Infection

In previous sections, we have discussed how metabolic pathways can be changed upon virus infection and how host intrinsic metabolic activities and extrinsic events that affect metabolism can influence the expression of infection. These situations raise the issue as to whether manipulating one or more aspects of host metabolism represent useful and perhaps convenient approaches to control the outcome of virus infections. They might be especially useful with infections not well controlled by vaccines or antiviral drugs. Currently, the majority of reports that target metabolism for disease control have dealt with autoimmunity or cancer, but viral diseases especially chronic persistent infections, could be a fruitful field for investigation. With respect to virus infections, the great majority of studies on metabolic manipulations have been performed in-vitro with various drugs (Figure 2) and many of these are recorded in Table 2. As mentioned in-vivo studies are sparse. An early report came from the Medzhitov laboratory which was designed to compare the effects of calorie restriction on some viral and bacterial infections. The study showed that anorexia made neurogenic flu infections more severe, but protected against bacterial sepsis infections. Moreover, nutritional supplementation with glucose was detrimental to bacterial disease, but protected against lethal flu infection. In their models, the nutritional effects were explained not by effects on immune function, but by an ER stress effects on the brain with this causing more apoptosis in neuronal cells (167).

Another study looked at the in-vivo consequences of interfering with glucose utilization using 2DG (2-deoxy-D-glucose) therapy in a viral disease model (168). Inhibition of glucose utilization resulted in diminished HSV induced inflammatory lesions in the eye (168). The protective therapy was explained by a reduction in proinflammatory T cell activity that primarily use glycolysis to supply their energy. In this study, the Treg responses, which were shown previously to suppress the severity of ocular lesions (168), was not affected by 2DG therapy. Accordingly, metabolic manipulation, such as reprogramming glucose metabolism, can represent an approach to control the expression of viral inflammatory disease. Other reports on this topic have also appeared (163).

Another potential metabolic target that has promise to control the extent of a virus infection is fatty acid metabolism which is a crucial event for many viruses such as flaviviruses that depend on cellular lipids to complete their life cycle. Success at controlling several human flavivirus disease agents has been achieved in-vitro using inhibitors of acetyl coenzyme carboxylase, which is essential for de novo lipogenesis (169). So far studies on in-vivo effects have only been done using a mouse model of West Nile fever (WNF). In such studies, the infection was successfully controlled including lesions in the kidney (169). The latter is relevant since renal complications are a prominent feature of persistent WNF infection in humans (170).

Another metabolic step accessible for inhibition to suppress viral diseases is glutamine metabolism. Thus this amino acid is used to support proliferation and cytokine producing activity of inflammatory T cells and in addition is a precursor of a neurotoxic molecule, glutamate. Inhibiting glutamine metabolism was shown to be valuable to diminish CNS inflammatory lesions caused by Sindbis virus infection (171). Inhibiting glutamine metabolism could well be an approach to control other immunoinflammatory viral lesions and our group is exploring its values to limit herpetic stromal keratitis lesions.

We anticipate that additional approaches to manipulate metabolism will be useful to shape the outcome of virus infections particularly when used along with other therapies such as antiviral and anti-inflammatory drugs.

Conclusions

Controlling virus infections is most effectively achieved using vaccines and with a few viruses specific anti-viral drugs. However, such approaches are not available for many infections, which includes COVID-19, the cause of a current pandemic. We need new approaches to control virus infections and this review focusses on changing the metabolic events that occur during viral infections. We advocate that manipulating metabolic activities represent a useful approach to control the outcome of some viral infections that may include COVID-19 infection. We described how metabolic changes are set into play by different viral infections and point out that changing the metabolic environment might be one means of controlling if the virus host relationship is productive and tissue damaging or inapparent. We also review how the outcome of virus infections can be affected by the metabolic status of the host. Particularly relevant are DM and obesity that impact on the clinical consequences of infections such as Flu and COVID-19 infection. In addition, the nutritional status of the host may also influence the expression of some virus infections and changing the diet holds promise as one way to control the outcome of some viral infections. The major question addressed was whether it is possible to reshape the outcome of a viral infection, particularly those where the host response contributes to tissue damage. The topic has received minimal investigation, but some studies do show that controlling events such as glycolysis, glutaminolysis and fatty acid metabolism are showing promise as an approaches to limit the severity of some viral infections. We presume that manipulating metabolism to reshape the nature of some virus infections will become a valuable addition to the current approaches available to control virus infections.

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