Surfactant Protein-A and Type 2 Asthma in SARS-CoV-2 Infection

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During the first cycle of our AADCRC program, our project focused primarily on Surfactant Protein A (SP-A), a known innate immune modulator that exhibits important anti-inflammatory effects in asthma. In this renewal, we show preliminary data that SP-A binds the interleukin (IL)-6 receptor and disrupts IL-6 signaling, events relevant to specific asthma phenotypes. While this work was progressing, the Severe Acute Respiratory Syndrome- related Coronavirus 2 (SARS-CoV-2)-driven coronavirus disease 2019 (COVID-19) pandemic emerged and has fundamentally changed our world. Elevated serum IL-6 is a hallmark of the “cytokine storm” associated with severe COVID-19 acute respiratory distress and IL-6 inhibitors show promise as treatments. Our data suggest that SP-A exhibits innate functions relevant to SARS-CoV-2 infection by inhibiting IL-6 signaling intermediates and also by binding to angiotensin converting enzyme-2 (ACE2), the receptor used by SARS-CoV-2 for entry into host cells. These findings suggest that SP-A may attenuate the inappropriate innate immune responses in COVID-19 and by this mechanism, could play a role in the treatment of SARS-CoV-2 infection. Several chronic lung-based comorbidities have been shown to increase the severity and mortality associated with COVID-19 - with the notable exception of asthma. Evidence from our group suggests that type-2 (T2) cytokines such as IL-4 and IL-13, which are critical molecular underpinnings of atopic asthma, reduce ACE2 expression in airway epithelial cells from T2 asthma. These findings suggest that atopic asthma-associated T2 cytokines protect against COVID-19 by modulating infection. In this AADCRC renewal, we will build on these preliminary data and merge two complementary, unique lines of investigation to expand the focus of our proposal and investigate the interplay of SP-A and T2 cytokines at both the initiation and the effector stages of SARS- CoV-2 respiratory tract infection in asthma. We will test the novel hypothesis that SP-A effectively limits COVID- 19 by decreasing ACE2-mediated events through direct receptor binding and inhibition of IL-6 signaling pathways. In the setting of atopic asthma, type-2 cytokines may reduce the susceptibility to SARS-CoV- 2 infection by inhibiting ACE2 expression and function. In aim 1, we will determine the impact of SP-A in limiting SARS-CoV-2 infection of human nasal, bronchial and distal airway epithelial cells and whether these effects depend upon ACE2 binding and modulation of IL-6 signaling. In aim 2, we will assess ACE2 expression in nasal, bronchial and distal epithelial cells from normal atopic and non-atopic controls and T2 asthmatic participants, and determine how T2 cytokines and virus-induced interferons interact to regulate epithelial cell ACE2 expression and SARS-CoV-2 infection in these cells. We hypothesize that SP-A and T2 cytokines can synergize to dampen both the initiation and the effector phases of SARS-CoV-2 infection, thereby protecting from COVID-19. This proposal leverages expertise in asthma, SP-A immune responses, virology and epithelial biology within the project and synergizes well with Projects 1 and 2 to better understand viral insults in asthma.