Direct Inhibition of Cellular Fatty Acid Synthase Impairs Replication of Respiratory Syncytial Virus and Other Respiratory Viruses

Ohol, Yamini M.; Wang, Zhaoti; Kemble, George; Duke, Gregory

doi:10.1371/journal.pone.0144648

Cited by 52 publications

(50 citation statements)

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“…In the vast array of possible paths toward a working therapeutic, inhibition of host proteases to affect viral infection and replication has advantages; host genes have lower mutation frequencies and therefore reduce the risk of acquiring drug resistance, which has been demonstrated for RSV with an inhibitor developed against Hsp90 [17]. Inhibiting host proteases may also provide the possibility to inhibit multiple viruses that rely on the same protease for their replication cycle, offering the potential for broad-spectrum anti-viral activity [17,18].…”

Section: Discussionmentioning

confidence: 99%

“…In this view, host proteases which have been shown to be involved in many viral activities such as uncoating, viral protein production and post-translational modifications, provide potential antiviral targets through the use of protease inhibitors. The advantage of developing inhibitors for host proteins is that they generally have a reduced risk for the induction of drug resistance [17,18]. For viruses such as Ebola [19], HCV, HIV [20], Influenza [21] and MERS [22], host proteases have been described that play an essential role in virus replication, allowing the use of specific protease inhibitors to reduce the infection.…”

Section: Introductionmentioning

confidence: 99%

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Respiratory syncytial virus (RSV) entry is inhibited by serine protease inhibitor AEBSF when present during an early stage of infection

Gucht

Leemans

Schryver

et al. 2017

Virol J

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BackgroundHost proteases have been shown to play important roles in many viral activities such as entry, uncoating, viral protein production and disease induction. Therefore, these cellular proteases are putative targets for the development of antivirals that inhibit their activity. Host proteases have been described to play essential roles in Ebola, HCV, HIV and influenza, such that specific protease inhibitors are able to reduce infection. RSV utilizes a host protease in its replication cycle but its potential as antiviral target is unknown. Therefore, we evaluated the effect of protease inhibitors on RSV infection.MethodsTo measure the sensitivity of RSV infection to protease inhibitors, cells were infected with RSV and incubated for 18 h in the presence or absence of the inhibitors. Cells were fixed, stained and studied using fluorescence microscopy.ResultsSeveral protease inhibitors, representing different classes of proteases (AEBSF, Pepstatin A, E-64, TPCK, PMSF and aprotinin), were tested for inhibitory effects on an RSV A2 infection of HEp-2 cells. Different treatment durations, ranging from 1 h prior to inoculation and continuing for 18 h during the assay, were evaluated. Of all the inhibitors tested, AEBSF and TPCK significantly decreased RSV infection. To ascertain that the observed effect of AEBSF was not a specific feature related to HEp-2 cells, A549 and BEAS-2B cells were also used. Similar to HEp-2, an almost complete block in the number of RSV infected cells after 18 h of incubation was observed and the effect was dose-dependent. To gain insight into the mechanism of this inhibition, AEBSF treatment was applied during different phases of an infection cycle (pre-, peri- and post-inoculation treatment). The results from these experiments indicate that AEBSF is mainly active during the early entry phase of RSV. The inhibitory effect was also observed with other RSV isolates A1998/3–2 and A2000/3–4, suggesting that this is a general feature of RSV.ConclusionRSV infection can be inhibited by broad serine protease inhibitors, AEBSF and TPCK. We confirmed that AEBSF inhibition is independent of the cell line used or RSV strain. The time point at which treatment with the inhibitor was most potent, was found to coincide with the expected moment of entry of the virion with the host cell.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Respiratory syncytial virus (RSV) entry is inhibited by serine protease inhibitor AEBSF when present during an early stage of infection

Gucht

Leemans

Schryver

et al. 2017

Virol J

View full text Add to dashboard Cite

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“…Indeed, blocking de novo synthesis of palmitate by inhibiting FA synthase impairs replication of several respiratory RNA viruses. 32 Furthermore, many RNA viruses perturb cholesterol homeostasis. Statins, which are drugs targeting the rate-limiting step of cholesterol biosynthesis, have off-target effects that may reduce IAV infection symptoms, secondary pneumonia, and morbidity in humans.…”

mentioning

confidence: 99%

Fueling influenza and the immune response: Implications for metabolic reprogramming during influenza infection and immunometabolism

Bahadoran

Bezavada

Smallwood

2020

Immunological Reviews

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The metabolic impact of influenza A virus (IAV) infections on immune cells remains largely uncharacterized. However, much is known about the metabolism of IAV infection and immunometabolism. Thus, we will consider four main factors: the metabolic requirements of influenza virus, metabolic reprogramming of immune cells that are mobilized to fight IAV infection, the impact of systemic or local metabolism on the infection and immune response, and vice versa. We will also address the interplay of metabolism and cytokines with a focus on those relevant to IAV infections. Finally, we will limit information on immunometabolism to key cell types critical to fighting IAV infection. We will relate this information to the unique metabolic demands on immune cells and discuss how their translocation through nutrient diverse and changing environments may affect their functions in IAV infection. | ME TABOLIS M AND THE LUNG MICROENVIRONMENT | Steady-state metabolismUnder aerobic conditions, cells sustain themselves catabolically using glycolytic carbons to fuel the tricarboxylic acid (TCA) cycle. AbstractRecent studies support the notion that glycolysis and oxidative phosphorylation are rheostats in immune cells whose bioenergetics have functional outputs in terms of their biology. Specific intrinsic and extrinsic molecular factors function as molecular potentiometers to adjust and control glycolytic to respiratory power output. In many cases, these potentiometers are used by influenza viruses and immune cells to support pathogenesis and the host immune response, respectively. Influenza virus infects the respiratory tract, providing a specific environmental niche, while immune cells encounter variable nutrient concentrations as they migrate in response to infection. Immune cell subsets have distinct metabolic programs that adjust to meet energetic and biosynthetic requirements to support effector functions, differentiation, and longevity in their ever-changing microenvironments. This review details how influenza coopts the host cell for metabolic reprogramming and describes the overlap of these regulatory controls in immune cells whose function and fate are dictated by metabolism. These details are contextualized with emerging evidence of the consequences of influenzainduced changes in metabolic homeostasis on disease progression. K E Y W O R D Shost pathogen, immune response, Immunometabolism, Influenza, metabolism, viral infection, virus | 141 BAHADORAN et Al.

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“…15. Various RSV infection controls have been reported in the literature, including the use of cell lysate [13], vehicle [19], PBS [20], or UV-inactivated virus [21]. In our hands, the use of cell lysate elicits early, subtle increases in macrophage MHC class II expression, whereas MEM (vehicle) does not.…”

mentioning

confidence: 66%

“…Pick several fourth round plaques that can be frozen as well. 19. Grow and harvest stock as per working stock protocol.…”

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confidence: 99%

Mouse Models of Viral Infection

Empey

Peebles

Janssen

2018

Methods in Molecular Biology

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Viral respiratory tract infections are common in both children and adults. Mouse models of viral infection enable the characterization of host immune factors that protect against or promote virus infection; thus, mouse models are essential for interrogation of potential therapeutic targets. Moreover, they serve as critical models for the development of novel vaccine strategies. In this chapter, we describe methods for establishing mouse models of respiratory syncytial virus (RSV) and H1N1 influenza A virus infection. Protocols are provided for viral culture and expansion, plaque-forming assays for viral quantification, and infection of mice. Alternate modifications to the models are also described, and their potential impact is discussed.

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Direct Inhibition of Cellular Fatty Acid Synthase Impairs Replication of Respiratory Syncytial Virus and Other Respiratory Viruses

Cited by 52 publications

References 48 publications

Respiratory syncytial virus (RSV) entry is inhibited by serine protease inhibitor AEBSF when present during an early stage of infection

Respiratory syncytial virus (RSV) entry is inhibited by serine protease inhibitor AEBSF when present during an early stage of infection

Fueling influenza and the immune response: Implications for metabolic reprogramming during influenza infection and immunometabolism

Mouse Models of Viral Infection

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