Roles of sex and SP-A genetic variants in modulating multiorgan injuries post viral infection.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), and multi-organ dysfunction (MOD). Human surfactant protein A (SP-A), a key component of innate immunity, exhibits genetic polymorphisms that may influence host responses to viral infection. Human patient studies have shown that biological sex has been associated with differences in COVID-19 severity. However, the combined effects of SP-A variants and sex on SARS-CoV-2-induced organ injury remain poorly understood. METHODS: We utilized double-humanized transgenic mice expressing human ACE2 and individual human SP-A variants (6A2, 6A4, 1A0, 1A3), alongside SP-A knockout (KO) and wild-type (K18) controls. Male and female mice were intranasally infected with SARS-CoV-2 (Delta variant) and assessed on day 6 post-infection. Histopathological analyses were performed to evaluate lung, kidney, and intestinal injury. In parallel, in vitro assays assessed SP-A variant binding to viral spike (S) protein and receptor-binding domain (RBD), as well as effects on viral infectivity in lung epithelial cells. RESULTS: SP-A variants significantly attenuated SARS-CoV-2-induced organ injury compared to KO mice, with SP-A variant and organ-specific effects. In the lung, injury severity followed the order 6A2 > 1A0 > K18 > 1A3 > 6A4, with female mice, particularly those expressing 1A3 and 6A4, exhibiting markedly reduced ALI compared to males. In the kidney, 1A0 and 6A4 variants showed the greatest protection, again with stronger effects in females. In contrast, intestinal injury was attenuated by SP-A variants independent of sex. Across tissues, SP-A deficiency was associated with increased viral burden and inflammation. Mechanistically, SP-A variants differentially bound SARS-CoV-2 S protein and RBD, with the 1A0 variant demonstrating the stronger binding and greater inhibition of viral infectivity compared to 6A2 variant in vitro. CONCLUSIONS: Human SP-A genetic variants and biological sex interact to modulate SARS-CoV-2-induced multi-organ injury in a tissue-specific manner. These findings highlight the importance of host genetic variation in innate immunity and suggest that SP-A variants, together with sex-specific considerations, may inform risk stratification and therapeutic strategies for COVID-19 and related viral diseases.