Differential Immunoregulation by Human Surfactant Protein A Variants Determines Severity of SARS-CoV-2-induced Lung...

COVID-19 remains a significant threat to public health globally. Infection in some susceptible individuals causes life-threatening acute lung injury (ALI/ARDS) and/or death. Human surfactant protein A (SP-A) is a C-type lectin expressed in the lung and other mucosal tissues, and it plays a critical role in host defense against various pathogens. The human SP-A genes ( SFTPA1 and SFTPA2 ) are highly polymorphic and comprise several common genetic variants, i.e., SP-A1 (variants 6A ² , 6A ⁴ ) and SP-A2 (variants 1A ⁰ , 1A ³ ). Here, we elucidated the differential antiviral and immunoregulatory roles of SP-A variants in response to SARS-CoV-2 infection in vivo . Six genetically-modified mouse lines, expressing both hACE2 (SARS-CoV-2 receptor) and individual SP-A variants: (hACE2/6A ² (6A ² ), hACE2/6A ⁴ (6A ⁴ ), hACE2/1A ⁰ (1A ⁰ ), and hACE2/1A ³ (1A ³ ), one SP-A knockout (hACE2/SP-A KO (KO) and one hACE2/mouse SP-A (K18) mice, were challenged intranasally with 10 ³ PFU SARS-CoV-2 or saline (Sham). Infected KO and 1A ⁰ mice had more weight loss and mortality compared to other mouse lines. Relative to other infected mouse lines, a more severe ALI was observed in KO, 1A ⁰ , and 6A ² mice. Reduced viral titers were generally observed in the lungs of infected SP-A mice relative to KO mice. Transcriptomic analysis revealed an upregulation in genes that play central roles in immune responses such as MyD88 , Stat3 , IL-18 , and Jak2 in the lungs of KO and 1A ⁰ mice. However, Mapk1 was significantly downregulated in 6A ² versus 1A ⁰ mice. Analysis of biological pathways identified those involved in lung host defense and innate immunity, including pathogen-induced cytokine, NOD1/2, and Trem1 signaling pathways. Consistent with the transcriptomic data, levels of cytokines and chemokines such as G-CSF, IL-6 and IL-1β were comparatively higher in the lungs and sera of KO and 1A ⁰ mice with the highest mortality rate. These findings demonstrate that human SP-A variants differentially modulate SARS-CoV-2-induced lung injury and disease severity by differentially inhibiting viral infectivity and regulating immune-related gene expressions.