Role of Mouse Hepatitis Virus (MHV) Receptor Murine CEACAM1 in the Resistance of Mice to MHV Infection: Studies of Mice with Chimeric mCEACAM1a and mCEACAM1b

Abstract

Although most inbred mouse strains are highly susceptible to mouse hepatitis virus (MHV) infection, the inbred SJL line of mice is highly resistant to its infection. The principal receptor for MHV is murine CEACAM1 (mCEACAM1). Susceptible strains of mice are homozygous for the 1a allele of mCeacam1, while SJL mice are homozygous for the 1b allele. mCEACAM1a (1a) has a 10-to 100-fold-higher receptor activity than does mCEACAM1b (1b). To explore the hypothesis that MHV susceptibility is due to the different MHV receptor activities of 1a and 1b, we established a chimeric C57BL/6 mouse (cB61ba) in which a part of the N-terminal immunoglobulin (Ig)-like domain of the mCeacam1a (1a) gene, which is responsible for MHV receptor function, is replaced by the corresponding region of mCeacam1b (1b). We compared the MHV susceptibility of these chimeric mice to that of SJL and B6 mice. B6 mice that are homozygous for 1a are highly susceptible to MHV-A59 infection, with a 50% lethal dose (LD 50 ) of 10 2.5 PFU, while chimeric cB61ba mice and SJL mice homozygous for 1ba and 1b, respectively, survived following inoculation with 10 5 PFU. Unexpectedly, cB61ba mice were more resistant to MHV-A59 infection than SJL mice as measured by virus replication in target organs, including liver and brain. No infectious virus or viral RNA was detected in the organs of cB61ba mice, while viral RNA and infectious virus were detected in target organs of SJL mice. Furthermore, SJL mice produced antiviral antibodies after MHV-A59 inoculation with 10 5 PFU, but cB61ba mice did not. Thus, cB61ba mice are apparently completely resistant to MHV-A59 infection, while SJL mice permit low levels of MHV-A59 virus replication during self-limited, asymptomatic infection. When expressed on cultured BHK cells, the mCEACAM1b and mCEACAM1ba proteins had similar levels of MHV-A59 receptor activity. These results strongly support the hypothesis that although alleles of mCEACAM1 are the principal determinants of mouse susceptibility to MHV-A59, other as-yet-unidentified murine genes may also play a role in susceptibility to MHV.

Structure, Function, and Evolution of Coronavirus Spike Proteins

“…Critical RBM residues are conserved in the S1-NTDs from different MHV strains, including hepatotropic strain A59 and neurotropic strain JHM, allowing these MHV strains to use CEACAM1 as their receptor (94). Several critical VBM residues differ between two forms of CEACAM1 encoded by mice, CEACAM1a and CEACAM1b, rendering CEACM1a, but not CEACAM1b, as an effective receptor for MHV (95)(96)(97). CEACAM1a molecules from mouse, cattle, and human also differ in several critical VBM residues, presenting a barrier for cross-species transmissions of MHV (88).…”

Receptor Recognition Mechanisms of Coronaviruses: a Decade of Structural Studies

“…HCoV-NL63 from the ␣-genus is a prevalent human respiratory pathogen that is often associated with common colds in healthy adults and acute respiratory diseases in young children (10,11). Among the animal coronaviruses, TGEV from the ␣-genus and MHV from the ␤-genus cause close to 100% fatality in young pigs and young mice, respectively (12)(13)(14)(15); BCoV from the ␤-genus and IBV from the ␥-genus also cause significant health damage in cattle and chickens, respectively (16)(17)(18)(19). Therefore, research on coronaviruses has strong health and economic implications.…”

Structural and Molecular Evidence Suggesting Coronavirus-driven Evolution of Mouse Receptor

“…Correspondingly, mice homozygous for Ceacam1b (1b/1b) are resistant to death from MHV infections, whereas mice homozygous for Ceacam1a (1a/1a) are highly susceptible to lethal MHV infections (7,9,10,20,21). Other than their different MHV receptor activities, mCEACAM1a and mCEACAM1b appear to be functionally equivalent: neither 1a/1a mice nor 1b/1b mice show any growth defects, whereas a dysfunctional Ceacam1 gene leads to impaired insulin clearance, abnormal weight gain, and reduced fertility (22). Our previous structural studies of mCEACAM1a and its complex with MHV S1-NTD have delineated detailed interactions between mCEACAM1a and MHV S1-NTD (15,23).…”