Dysregulated T-Helper Type 1 (Th1):Th2 Cytokine Profile and Poor Immune Response in Pregnant Ferrets Infected With 2009 Pandemic Influenza A(H1N1) Virus

Abstract

Pregnancy has been associated with severe influenza, an association highlighted during the 2009 pandemic of influenza A(H1N1) virus (A[H1N1]pdm09) infection. To assess the underlying mechanism, we infected pregnant and non-pregnant ferrets with A(H1N1) pdm09 virus. A(H1N1)pdm09-infected pregnant ferrets also had higher levels of inflammatory cytokines in their pulmonary tracts. Systemically, total CD8+ T cell counts and A(H1N1)pdm09-specific B-cell responses in blood were significantly lower in pregnant ferrets. This model predicts that the poorer outcome for pregnant women during the A(H1N1)pdm09 pandemic was due to an elevated level of viral replication and to a cytokine imbalance that led to a less effective immune response.

CD4+T follicular helper (Tfh) cells in human tonsil and blood are clonally convergent, but divergent from non-Tfh CD4+cells

“…The number of HA-specific clones generated from the cTfh CXCR3 + and cNon-Tfh compartments was also much higher than that generated from the cTfh CXCR3pool. The CD4 + CXCR3 + bias in the HA-specific response is in line with previous reports (Palladino et al, 1991;Pedersen et al, 2014;Valkenburg et al, 2018;Yang et al, 2013;Yoon et al, 2017;Zielinski et al, 2011). Notably, in one of the 3 donors studied, the TCR sequences of blood-derived HA-specific cTfh CXCR3 + clones were found in the tTfh CXCR3 + repertoire, supporting a common clonal origin of antigen-specific Tfh cells in tonsil and the circulation.…”

Ferreting Out Influenza Virus Pathogenicity and Transmissibility: Past and Future Risk Assessments in the Ferret Model

“…That said, it is known that prior exposure(s) to influenza virus (achieved by either prior infection, vaccination, or both) can shape the resulting host response to the infection (Laurie et al 2010;Pearce et al 2012a;Kirchenbaum et al 2016). Furthermore, altered health states of the host (including age, pregnancy, and immunosuppression) are known to greatly influence the duration of virus shedding, disease progression, and emergence of antiviral resistance and have been modeled in ferrets (Paquette et al 2014;Roosenhoff et al 2018;Yoon et al 2018). Increased attention to the role the host microbiome plays in infection is similarly understudied in the ferret model.…”

Influenza in High-Risk Hosts—Lessons Learned from Animal Models

“…Increased expression of pro-inflammatory cytokines IL-1α, IL-6, IL-12, TNF-α, G-CSF, RANTES, and MCP-1, increased immunosuppressive cytokines IL-10 and IFN-γ, and type I and III IFNs reduction together alter the cellular microenvironment of the maternal lung and promote severe immunopathology-alterations that are compounded as pregnancy advances (Gonzalez et al 2009;Chan et al 2010;Kraus et al 2010;Marcelin et al 2011;Forbes et al 2012;Kim et al 2012a;Zheng et al 2012;Vanders et al 2013). Pregnancy in the ferret model supports these findings, as increased inflammatory cytokines in the lungs lead to cytokine imbalance and elevated viral replication compared with nonpregnant, influenza virus-infected controls (Yoon et al 2018).…”

“…There is a dearth of knowledge on alterations to antibody-mediated immunity and B cells in influenza infection during pregnancy in animal models and human cohorts. Influenza infection in the pregnant ferret model does show reduced IgG-specific B-cell responses after experimental infection, although it remains to be determined if this occurs during natural infection in humans (Yoon et al 2018). Interestingly, the complement pathway components C3, C3a, and C4 show diminished antibody-dependent neutralization of influenza in pregnant African green monkeys (Mayer and Parks 2014).…”