Influenza A (H1N1) virus infection triggers severe pulmonary inflammation in lupus-prone mice following viral clearance

Abstract

Each year, up to one fifth of the United States population is infected with influenza virus. Although mortality rates are low, hundreds of thousands are hospitalized each year in the United States. Specific high risk groups, such as those with suppressed or dysregulated immune systems, are at greater danger for influenza complications. Respiratory infections are a common cause of hospitalizations and early mortality in patients with systemic lupus erythematosus (SLE); however, whether this increased infection risk is a consequence of the underlying dysregulated immune background and/or immunosuppressing drugs is unknown. To evaluate the influenza immune response in the context of lupus, as well as assess the effect of infection on autoimmune disease in a controlled setting, we infected lupus-prone MRL/MpJ-Faslpr mice with influenza virus A PR/8/34 H1N1. Interestingly, we found that Faslpr mice generated more influenza A virus specific T cells with less neutrophil accumulation in the lung during acute infection. Moreover, Faslpr mice produced fewer flu-specific IgG and IgM antibodies, but effectively cleared the virus. Further, increased extrinsic apoptosis during influenza infection led to a delay in autoimmune disease pathology with decreased severity of splenomegaly and kidney disease. Following primary influenza A infection, Faslpr mice had severe complications during the contraction and resolution phase with widespread severe pulmonary inflammation. Our findings suggest that influenza infection may not exacerbate autoimmune pathology in mice during acute infection as a direct result of virus induced apoptosis. Additionally, autoimmunity drives an enhanced antigen-specific T cell response to clear the virus, but persisting pulmonary inflammation following viral clearance may cause complications in this lupus animal model.

Key genes and functional coexpression modules involved in the pathogenesis of systemic lupus erythematosus

“…Virus infections, such as influenza, are very prevalent worldwide, and, thus, a better understanding of their roles in SLE is critical for the exploration the etiology of SLE. Some studies have proposed that viral infections can result in increased expressions of genes involving type I IFN system, which may further lead to SLE (Buskiewicz et al, 2016;Moal et al, 2013;Slight-Webb, Bagavant, Crowe, & James, 2015). There are also some observational studies on the link between virus infections and SLE (Hanlon, Avenell, Aucott, & Vickers, 2014;Rasmussen, Nielsen, Houen, & Jacobsen, 2016;Zandman-Goddard et al, 2009 Guiducci, & Coffman, 2007;Fagone, Muthumani, et al, 2014;Oon, Wilson, & Wicks, 2016).…”

COVID-19 in patients with systemic lupus erythematosus: lessons learned from the inflammatory disease

“…39,40 In comparison, Influenza A infection in lupus-prone Fas lpr mice is cleared effectively and is not associated with worsening autoimmune features in the acute setting, although these mice can subsequently develop severe pulmonary inflammation weeks after viral clearance. 41 Notably, annual vaccination against influenza is associated with decreased hospitalization and ICU admissions in patients with SLE; hence this practice is highly encouraged. 42 In addition to the increased susceptibility to certain viral infections in SLE, the role of exogenous viruses in triggering autoimmunity has also been proposed.…”

Influenza and sudden unexpected death: the possible role of peptide cross-reactivity

“…Disappointingly, the causal mechanistic and molecular links between influenza epidemics and SUD remain unknown, However, it has to be annotated that influenza has been implicated as a potential trigger for autoimmune diseases such as diabetes [14,15], severe pulmonary inflammation in lupus-prone mice [16], thrombocytopenia [14], atherogenesis [17,18], narcolepsy [19][20][21][22][23][24], brain autoimmunity [24], leukoencephalopathy [25], and neurological disorders and schizophrenia [26]. Moreover, the reports [5][6][7][8] that suggest a role of autoimmune processes in the development of influenza lesions in the myocardium are relevant in an immunological context.…”