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Defining Parameters That Modulate Susceptibility and Protection to Respiratory Murine Coronavirus MHV1 Infection
Journal article   Peer reviewed

Defining Parameters That Modulate Susceptibility and Protection to Respiratory Murine Coronavirus MHV1 Infection

Elvia E Silva, Steven J Moioffer, Mariah Hassert, Roger R Berton, Matthew G Smith, Stephanie van de Wall, David K Meyerholz, Thomas S Griffith, John T Harty and Vladimir P Badovinac
The Journal of immunology (1950), Vol.212(4), pp.563-575
02/15/2024
DOI: 10.4049/jimmunol.2300434
PMCID: PMC10872354
PMID: 38149923
url
https://pmc.ncbi.nlm.nih.gov/articles/PMC10872354/pdf/nihms-1949211.pdfView
Open Access

Abstract

Patients infected with SARS-CoV-2 experience variable disease susceptibility, and patients with comorbidities such as sepsis are often hospitalized for COVID-19 complications. However, the extent to which initial infectious inoculum dose determines disease outcomes and whether this can be used for immunological priming in a genetically susceptible host has not been completely defined. We used an established SARS-like murine model in which responses to primary and/or secondary challenges with murine hepatitis virus type 1 (MHV-1) were analyzed. We compared the response to infection in genetically susceptible C3H/HeJ mice, genetically resistant C57BL/6J mice, and genetically diverse, variably susceptible outbred Swiss Webster mice. Although defined as genetically susceptible to MHV-1, C3H/HeJ mice displayed decreasing dose-dependent pathological changes in disease severity and lung infiltrate/edema, as well as lymphopenia. Importantly, an asymptomatic dose (500 PFU) was identified that yielded no measurable morbidity/mortality postinfection in C3H/HeJ mice. Polymicrobial sepsis induced via cecal ligation and puncture converted asymptomatic infections in C3H/HeJ and C57BL/6J mice to more pronounced disease, modeling the impact of sepsis as a comorbidity to β-coronavirus infection. We then used low-dose infection as an immunological priming event in C3H/HeJ mice, which provided neutralizing Ab-dependent, but not circulating CD4/CD8 T cell-dependent, protection against a high-dose MHV-1 early rechallenge. Together, these data define how infection dose, immunological status, and comorbidities modulate outcomes of primary and secondary β-coronavirus infections in hosts with variable susceptibility.

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