Innate Immunity and Influenza A Virus Pathogenesis: Lessons for COVID-19

Abstract

There is abundant evidence that the innate immune response to influenza A virus (IAV) is highly complex and plays a key role in protection against IAV induced infection and illness. Unfortunately it also clear that aspects of innate immunity can lead to severe morbidity or mortality from IAV, including inflammatory lung injury, bacterial superinfection, and exacerbation of reactive airways disease. We review broadly the virus and host factors that result in adverse outcomes from IAV and show evidence that inflammatory responses can become damaging even apart from changes in viral replication per se, with special focus on the positive and adverse effects of neutrophils and monocytes. We then evaluate in detail the role of soluble innate inhibitors including surfactant protein D and antimicrobial peptides that have a potential dual capacity for down-regulating viral replication and also inhibiting excessive inflammatory responses and how these innate host factors could possibly be harnessed to treat IAV infection. Where appropriate we draw comparisons and contrasts the SARS-CoV viruses and IAV in an effort to point out where the extensive knowledge existing regarding severe IAV infection could help guide research into severe COVID 19 illness or vice versa.

Keywords: LL-37; SARS-CoV; cytokine storm; defensin; influenza; neutrophil; pandemic; surfactant protein D.

Figure 1

Schema for possible stages of IAV infection. IAV initially encounters a number of constitutive barriers to infection, followed by locally elicited responses which help contain the virus, prevent spread to the lung, and begin to trigger adaptive immune responses. The principle role of the early innate response is to limit viral replication and minimize inflammation until adaptive response ensues. Depending on characteristics of the viral strain (e.g., pandemic vs. seasonal, HA characteristics) and host factors (e.g., immune deficiency, underlying inflammatory bias) the infection may not be well-contained leading to more inflammation and ultimately lung infection which can lead to profound illness through excessive inflammatory responses and possibly bacterial superinfection. The figure highlights the role of soluble inhibitors, monocyte/macrophages, and neutrophils which are emphasized in this review. The confocal microscope picture shows neutrophils treated in vitro with IAV and forming NETS. Green stain highlights neutrophil plasma membranes, blue stain highlights nuclei and cell free DNA, and red stain indicates virus.

Figure 2

(A) Illustrates construction of viruses differing from H1 (black colored) only is thus HA molecules. (B–D) Analysis of weight loss in mice infected with modified avian strains differing only in their HA molecules. Note that viruses contained the H1PB2-627E, H6, H7, H10, and H15 HA caused massive weight loss. This was accompanied by loss of resident macrophages and marked influx of neutrophils and inflammatory macrophages, pathogenic effects on human bronchial epithelial cells in culture and ultimate mortality. Viruses containing H2, H3, H5, H9, H11, H13, H14, and H16 HA were not pathogenic. Note that the pathogenic H1 virus was modified to contain a PB2 E627K mutation which is needed for mouse adaptation. Two different H7 strains were tested and they were similarly pathogenic. Only the H3 strain was inhibited by SP-D in vitro in this paper. These experiments implicate that IAV HA from different avian subtypes contains important virulence factors apart from other viral genes and that the HA can drive inflammatory myeloid cell infiltration. This figure was obtained and adapted (Qi et al., 2014). Use is allowed if properly cited.

Figure 3

Ribbon representations of H3, H2, and H6 hemagglutinins showing extensive van der Waals contacts for the 165 glycan on H3 HA but not for glycans found on H2 or H6 HA. Crystal structures of H3 (A), H2 (B), and H6 (C) HA molecules were compared. Van der Waals contacts between the glycans and neighboring amino acids are shown as black dashed lines. Separate HA subunits are in wheat and pale cyan. The red stripe in panels B and C indicates the position of the key glycan for SP-D attachment at N165 in H3 hemagglutinin. The reduced amount of Van der Waals contacts for glycans found on H2 and H6 HA allows for processing by Golgi and ER enzymes such that the resulting glycan is complex rather than high mannose and hence not susceptible for binding by SP-D. This explains failure of SP-D to bind or inhibit these strains. This figure was obtained and adapted (Parsons et al., 2020) with permission allowed with proper citation.

Figure 4

Validation of porcinized human SP-D as an antiviral agent against pandemic IAV infection in mice. The protective potential of porcinized human SP-D (iSP-D) against pandemic IAV infection was demonstrated in vivo (mouse model). Three different experiments were executed with 4 different conditions within each experiment; group size was n = 6 per condition. The A/California/E9/09 (H1N1) strain was inoculated along with either iSP-D or wild type human SP-D (hSP-D). Results in (A,B) show weights and virus titers, respectively for mice treated with PBS alone, Virus alone, iSP-D alone or iSP-D plus virus. (B,C) Show similar effects of two batches of iSP-D as compared to hSP-D. iSP-D provided significant protective effects which were greater than those provided by hSP-D which does not significantly inhibit this strain of virus in vitro. Statistical comparisons between experimental groups were made by Student's two-tailed paired t-test. *p < 0.05; **p < 0.005; ***p < 0.0005. This figure was obtained and adapted from (van Eijk et al., 2019) with permission allowed with proper citation.