A paucigranulocytic asthma host environment promotes the emergence of virulent influenza viral variants

Abstract

Influenza virus has a high mutation rate, such that within one host different viral variants can emerge. Evidence suggests that influenza virus variants are more prevalent in pregnant and/or obese individuals due to their impaired interferon response. We have recently shown that the non-allergic, paucigranulocytic subtype of asthma is associated with impaired type I interferon production. Here, we seek to address if this is associated with an increased emergence of influenza virus variants. Compared to controls, mice with paucigranulocytic asthma had increased disease severity and an increased emergence of influenza virus variants. Specifically, PB1 mutations exclusively detected in asthmatic mice were associated with increased polymerase activity. Furthermore, asthmatic host-derived virus led to increased disease severity in wild-type mice. Taken together, these data suggest that at least a subset of patients with asthma may be more susceptible to severe influenza and may be a possible source of new influenza virus variants.

Single-cycle influenza virus vaccine generates lung CD8 + Trm that cross-react against viral variants and subvert virus escape mutants

“…Escape mutants are common for chronic infections including human immunodeficiency virus (HIV) ( 39 ) and lymphocytic choriomeningitis virus ( 40 ). While influenza is generally an acute infection, CTL escape mutants are detected in both mouse models and humans ( 24 , 28 , 29 , 41 – 43 ). Relevant to our presented murine studies, others have shown that CD8 + CTL responses directed against influenza virus NP can exert selective pressure on the virus, and variants containing point mutations in the NP 366–374 epitope readily emerge ( 28 ).…”

Next-generation T cell–activating vaccination increases influenza virus mutation prevalence

“…Influenza A virus (IAV) is a highly mutable virus, as evidenced by continual antigenic drift, and antiviral escape that has rendered some drugs ineffective ( 9 ). Influenza virus diversification and adaptation have also been recently observed in an asthmatic mouse model ( 10 ) due to effects on the type I interferon response and for HA stem antibodies in human challenge studies ( 11 ). While T cell–targeted vaccines seem to be an optimal strategy for universal influenza vaccination, there is a potential for immune escape by viral adaptations.…”

“…Our knowledge is currently limited to inferences of immune escape for sequence databanks of human influenza isolates ( 15 , 27 ) and limited animal studies ( 10 , 14 ), which may underestimate the frequency of influenza T cell escape mutations. Less is known about within-host diversity during influenza infection ( 28 ) and the role of T cell–mediated immune pressure, especially in the context of universal vaccines that can be nonsterilizing compared to the standard of care, IIVs.…”

The influenza virus RNA polymerase as an innate immune agonist and antagonist

“…Similarly, innate immune activation can be induced by single mutations in the polymerase genes or combinations of mutations in one or more genes [24,32,33] (full list in Supplementary Table 2). Additional studies have shown that elimination of the interferon pressure during infection leads to substitution of conserved polymerase amino acids, indicating that the RNA polymerase amino acid composition is under a selection pressure from the immune response [34,35].…”