Differential roles of interferons in innate responses to mucosal viral infections

Walker, Forrest C.; Sridhar, Pratyush R.; Baldridge, Megan T.

doi:10.1016/j.it.2021.09.003

Cited by 59 publications

(61 citation statements)

References 164 publications

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“…As mentioned above, the different susceptibility of EIV/63 and EIV/2003 to the type I IFN response ( Fig 1D ) together with the distinct transcriptional changes induced by each virus on interferon-stimulated genes (ISGs) ( Fig 4A and B ) indicate that H3N8 EIV adaptation led to a more efficient escape to host pathogen recognition, as well as a more regulated control of the innate immune response. This is particularly important when considering that the innate immune response is the first line of defence against infections as it has direct antiviral effects [ 56 ], modulates downstream immune responses [ 57 ], and possesses proinflammatory properties [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

Long-term adaptation following influenza A virus host shifts results in increased within-host viral fitness due to higher replication rates, broader dissemination within the respiratory epithelium and reduced tissue damage

et al. 2021

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The mechanisms and consequences of genome evolution on viral fitness following host shifts are poorly understood. In addition, viral fitness -the ability of an organism to reproduce and survive- is multifactorial and thus difficult to quantify. Influenza A viruses (IAVs) circulate broadly among wild birds and have jumped into and become endemic in multiple mammalian hosts, including humans, pigs, dogs, seals, and horses. H3N8 equine influenza virus (EIV) is an endemic virus of horses that originated in birds and has been circulating uninterruptedly in equine populations since the early 1960s. Here, we used EIV to quantify changes in infection phenotype associated to viral fitness due to genome-wide changes acquired during long-term adaptation. We performed experimental infections of two mammalian cell lines and equine tracheal explants using the earliest H3N8 EIV isolated (A/equine/Uruguay/63 [EIV/63]), and A/equine/Ohio/2003 (EIV/2003), a monophyletic descendant of EIV/63 isolated 40 years after the emergence of H3N8 EIV. We show that EIV/2003 exhibits increased resistance to interferon, enhanced viral replication, and a more efficient cell-to-cell spread in cells and tissues. Transcriptomics analyses revealed virus-specific responses to each virus, mainly affecting host immunity and inflammation. Image analyses of infected equine respiratory explants showed that despite replicating at higher levels and spreading over larger areas of the respiratory epithelium, EIV/2003 induced milder lesions compared to EIV/63, suggesting that adaptation led to reduced tissue pathogenicity. Our results reveal previously unknown links between virus genotype and the host response to infection, providing new insights on the relationship between virus evolution and fitness.

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Section: Discussionmentioning

confidence: 99%

Long-term adaptation following influenza A virus host shifts results in increased within-host viral fitness due to higher replication rates, broader dissemination within the respiratory epithelium and reduced tissue damage

et al. 2021

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“…Similar to IFN-γ, the type-I IFN, IFN-α, is also a strong inducer of antiviral ISGs [ 49 , 60 , 66 , 75 ] and uncontrolled IFN-α responses have been associated with increased pathogenesis [ 51 , 52 , 70 , 71 ]. This study examined whether the kinetics of ISG responses to IFN-α treatment differed from that by IFN-γ in PBMCs ( Figure 6 ).…”

Section: Resultsmentioning

confidence: 99%

“…The IFN signaling pathway protects cells from invading viral pathogens by trans-activating a variety of interferon-stimulated genes (ISGs) [ 44 , 45 , 46 , 47 ]. Some ISGs encode innate detectors of viral molecules, while some encode effectors with varied antiviral functions, such as regulators of the apoptotic pathway, and IFN-signaling molecules [ 45 , 48 , 49 ]. Our studies and others suggest that a “fine-tuned” ISG response is critical for suppressing undesired, exaggerated viral responses, including HIV, that induce prolonged immune activation, and for preventing the consequential pathogenic host damages, while maintaining some innate antiviral activity [ 41 , 43 , 44 , 46 ].…”

Section: Introductionmentioning

confidence: 99%

Transient Increases in Inflammation and Proapoptotic Potential Are Associated with the HESN Phenotype Observed in a Subgroup of Kenyan Female Sex Workers

Gluchowski

Yu²,

Abrenica

et al. 2022

Viruses

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Interferon (IFN) -stimulated genes (ISGs) are critical effectors of IFN response to viral infection, but whether ISG expression is a correlate of protection against HIV infection remains elusive. A well-characterized subcohort of Kenyan female sex workers, who, despite being repeatedly exposed to HIV-1 remain seronegative (HESN), exhibit reduced baseline systemic and mucosal immune activation. This study tested the hypothesis that regulation of ISGs in the cells of HESN potentiates a robust antiviral response against HIV. Transcriptional profile of a panel of ISGs with antiviral function in PBMC and isolated CD4+ T cells from HESN and non-HESN sex worker controls were defined following exogenous IFN-stimulation using relative RT-qPCR. This study identified a unique profile of proinflammatory and proapoptotic ISGs with robust but transient responses to exogenous IFN-γ and IFN-α2 in HESN cells. In contrast, the non-HESN cells had a strong and prolonged proinflammatory ISG profile at baseline and following IFN challenge. Potential mechanisms may include augmented bystander apoptosis due to increased TRAIL expression (16-fold), in non-HESN cells. The study also identified two negative regulators of ISG induction associated with the HESN phenotype. Robust upregulation of SOCS-1 and IRF-1, in addition to HDM2, could contribute to the strict regulation of proinflammatory and proapoptotic ISGs in HESN cells. As reducing IRF-1 in the non-HESN cells resulted in the identified HESN ISG profile, and decreased HIV susceptibility, the unique HESN ISG profile could be a correlate of protection against HIV infection.

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“…These data suggest that either the increased viral load resulting from productive infection or the replication process per se, are endowed with immunostimulatory abilities, even in absence of type I IFN signaling. It should be noted that mice devoid of IFNARmediated signaling still express the ligands and receptors for type II (IFN-γ) and type III IFNs (IFN-λs), which may be prominently involved in the response to a viral challenge by immune or epithelial cell subsets, respectively [38,39]. The presence, functionality, and susceptibility to SARS-CoV-2-originated stimuli of the complementary IFN signaling systems in the IFNAR −/− may form the molecular basis for the here-observed alterations in gene expression patterns upon exposure to SARS-CoV-2 and/or upon its replication.…”

Section: Discussionmentioning

confidence: 99%

Modeling SARS-CoV-2 Infection in Mice Using Lentiviral hACE2 Vectors Infers Two Modes of Immune Responses to SARS-CoV-2 Infection

Katzman

Israely

Melamed

et al. 2021

Viruses

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a severe global pandemic. Mice models are essential to investigate infection pathology, antiviral drugs, and vaccine development. However, wild-type mice lack the human angiotensin-converting enzyme 2 (hACE2) that mediates SARS-CoV-2 entry into human cells and consequently are not susceptible to SARS-CoV-2 infection. hACE2 transgenic mice could provide an efficient COVID-19 model, but are not always readily available, and practically restricted to specific strains. Therefore, there is a dearth of additional mouse models for SARS-CoV-2 infection. We applied lentiviral vectors to generate hACE2 expression in interferon receptor knock-out (IFNAR1−/−) mice. Lenti-hACE2 transduction supported SARS-CoV-2 replication in vivo, simulating mild acute lung disease. Gene expression analysis revealed two modes of immune responses to SARS-CoV-2 infection: one in response to the exposure of mouse lungs to SARS-CoV-2 particles in the absence of productive viral replication, and the second in response to productive SARS-CoV-2 infection. Our results infer that immune response to immunogenic elements on incoming virus or in productively infected cells stimulate diverse immune effectors, even in absence of type I IFN signaling. Our findings should contribute to a better understanding of the immune response triggered by SARS-CoV-2 and to further elucidate COVID-19.

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Differential roles of interferons in innate responses to mucosal viral infections

Cited by 59 publications

References 164 publications

Long-term adaptation following influenza A virus host shifts results in increased within-host viral fitness due to higher replication rates, broader dissemination within the respiratory epithelium and reduced tissue damage

Long-term adaptation following influenza A virus host shifts results in increased within-host viral fitness due to higher replication rates, broader dissemination within the respiratory epithelium and reduced tissue damage

Transient Increases in Inflammation and Proapoptotic Potential Are Associated with the HESN Phenotype Observed in a Subgroup of Kenyan Female Sex Workers

Modeling SARS-CoV-2 Infection in Mice Using Lentiviral hACE2 Vectors Infers Two Modes of Immune Responses to SARS-CoV-2 Infection

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