Coinfection with SARS-CoV-2 and Influenza A Virus Increases Disease Severity and Impairs Neutralizing Antibody and CD4 ⁺ T Cell Responses

Abstract

Given the current COVID-19 pandemic, coinfection of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and influenza A virus (IAV) is a major concern for public health. However, the immunopathogenic events occurring with coinfections of SARS-CoV-2 and IAV remain unclear. Here, we report the pathogenic and immunological consequences of SARS-CoV-2 and IAV H1N1 coinfection in the K18-hACE2 transgenic mouse model. Compared to a single infection with SARS-CoV-2 or IAV, coinfections not only prolonged the primary virus infection period but also increased immune cell infiltration and inflammatory cytokine levels in bronchoalveolar lavage fluid leading to severe pneumonia and lung damage. Moreover, coinfections caused severe lymphopenia in peripheral blood, resulting in reduced total IgG, neutralizing antibody titers, and CD4 + T cell responses against each virus. This study sheds light on the immunopathogenesis of SARS-CoV-2 and IAV coinfection, which may guide the development of effective therapeutic strategies for the treatment of patients coinfected with these viruses. Importance The co-circulation of influenza virus merging with the COVID-19 pandemic raises a potentially severe threat to public health. Recently, increasing numbers of SARS-CoV-2 and influenza virus coinfection have been reported from many countries. It is a worrisome issue that SARS-CoV-2 coinfection with other pathogens may worsen the clinical outcome and severity of COVID-19 and increase fatality. Here, we evaluated SARS-CoV-2 and IAV coinfection using the K18-hACE2 mouse model. Coinfected mice exhibited increased mortality with a prolonged IAV shedding. Furthermore, coinfected mice showed a higher level of cytokines and chemokines compared to a single infection condition. Interestingly, our data show that coinfected mice showed significantly less amount of virus-specific and neutralizing antibodies than the mice with a single infection. Overall, this study suggests that coinfection aggravates viral pathology by impaired neutralizing antibody response.

The Host Response to Influenza A Virus Interferes with SARS-CoV-2 Replication during Coinfection

“…Experimental studies using hamsters and K18-hACE2 transgenic mice have examined the influence of coinfection on virus replication and disease severity ( 38 – 41 ). In K18-hACE2 mice, coinfection with SARS-CoV-2 and IAV resulted in increased disease severity, and both preinfection and coinfection with IAV resulted in higher SARS-CoV-2 viral loads in the lungs and nasal turbinate and delayed viral clearance ( 38 , 39 , 42 ). SARS-CoV-2 and IAV coinfection also resulted in increased disease severity compared to single infection in golden hamsters; however, unlike in the mouse model, coinfected hamsters exhibited lower SARS-CoV-2 viral loads in the lungs ( 41 ), similar to what was observed in the present study.…”

Priming With Rhinovirus Protects Mice Against a Lethal Pulmonary Coronavirus Infection

“…In contrast, an H3N2 strain of IAV was inhibited by SARS-CoV-2 coinfection in the hamster model ( 26 ). Additional studies in hACE2-transgenic mice and ferrets observed enhanced disease upon SARS-CoV2 and influenza virus coinfection ( 27 – 31 ). We have shown that when RV was given two days after IAV infection, mice succumbed to the infection faster than when given IAV alone ( 14 ).…”

SARS-CoV-2 and Influenza A virus: Dual diagnostics and vaccines

“…In a recent study, it has been found that 22.3% of SARS-CoV-2 positive dead cases in Iran were coinfection with influenza virus [ 7 ]. Kim et al [ 8 ] have used the K18-hACE2 transgenic mouse model to study the pathogenic and immunological effects of SARS-CoV-2 and IAV H1N1 coinfection. They have reported that SARS-CoV-2/IAV coinfections boosted immune cell infiltration and inflammatory cytokine levels in bronchoalveolar lavage fluid (BALF), resulting in severe pneumonia and lung injury ( Fig.…”

“…Hence, the coinfections can significantly increase the hospitalization, hence the mortality rate. Furthermore, coinfections also resulted in significant lymphopenia in the peripheral blood, with lower total IgG, neutralizing antibody titers, and CD4 + T cell responses to each virus [ 8 ]. Bai et al [ 9 ] have reported increased SARS-CoV-2 viral load, and more severe lung damage was observed in mice coinfected with IAV.…”

“…Recently, Toback et al [ 14 ] did not report any early safety concerns with the concomitant administration of a COVID-19 vaccine (NVX-CoV2373) with influenza vaccines (Flucelvax Quadrivalent; quadrivalent influenza cell-based vaccine for those aged 18–64 years and Fluad; adjuvanted trivalent influenza vaccine for those 65 years or older). The dual immunization of K18-hACE2 mice with H1N1 and SARS-CoV-2 effectively prevented them from both H1N1 and SARS-CoV-2 infection [ 8 ]. After infection with H1N1 and SARS-CoV-2, all the vaccinated mice survived.…”