Influenza Pathogenesis in Genetically Defined Resistant and Susceptible Murine Strains

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The murine infection model is a cornerstone for influenza virus research and includes aspects such as disease pathogenesis, immunobiology, and vaccine and antiviral drug development. One compelling feature of the murine model is the availability of inbred mouse strains, each with a unique genetic makeup and potential for variable responses to influenza infection. Using highly controlled infection studies, the response to influenza virus infection is classified on a spectrum from susceptible to resistant, reflecting severe morbidity and high mortality, to limited or no morbidity and no mortality. Although there have been a variety of studies establishing disparate pathogenesis amongst various murine strains, thus far, there is no consensus regarding the determinants of the outcome of infection. The goal of this review is to explore and discuss the differences in pathogenesis, as well as the innate and adaptive immune responses to influenza infection that have been described in susceptible and resistant mouse strains. Understanding how host genetics influences the response to influenza infection provides valuable insight into the variable responses seen in vaccine or drug efficacy studies, as well as indicates possible mechanisms contributing to increased disease severity in humans infected with influenza virus with no known risk factors.

Multiplexed screening of natural humoral immunity identifies antibodies at fine specificity for complex and dynamic viral targets.

Viral entry targets with therapeutic neutralizing potential are subject to multiple escape mechanisms, including antigenic drift, immune dominance of functionally irrelevant epitopes, and subtle variations in host cell mechanisms. A surprising finding of recent years is that potent neutralizing antibodies to viral epitopes independent of strain exist, but are poorly represented across the diverse human population. Identifying these antibodies and understanding the biology mediating the specific immune response is thus difficult. An effective strategy for meeting this challenge is to incorporate multiplexed antigen screening into a high throughput survey of the memory B cell repertoire from immune individuals. We used this approach to discover suites of cross-clade antibodies directed to conformational epitopes in the stalk region of the influenza A hemagglutinin (HA) protein and to select high-affinity anti-peptide antibodies to the glycoprotein B (gB) of human cytomegalovirus. In each case, our screens revealed a restricted VH and VL germline usage, including published and previously unidentified gene families. The in vivo evolution of paratope specificity with optimal neutralizing activity was understandable after correlating biological activities with kinetic binding and epitope recognition. Iterative feedback between antigen probe design based on structure and function information with high throughput multiplexed screening demonstrated a generally applicable strategy for efficient identification of safe, native, finely tuned antibodies with the potential for high genetic barriers to viral escape.