Question 1

SARS-CoV-2 Infection in Female and Male Microphysiological Models of Human Airways - Mark J. Mondrinos, PhD

Accepted Answer

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The goal of this research is to create male and female microphysiological models of human airways, which do not currently exist, and investigate sex differences in the response to SARS-CoV2 infection. The primary underpinning of this research is the clinical observation that women exhibit a decreased risk of developing acute respiratory distress syndrome (ARDS) upon SARS-CoV2 infection. We will create models of female and male airways by integrating human cells derived from female and male donors in 3-D culture devices that contain three individually addressable compartments for: i) culture of differentiated airway epithelial cells (AEC) at an air-liquid interface where the virus will be introduced; ii) 3D culture of lung fibroblasts (HLF) and myeloid immune cells; iii) perfusion culture of a pulmonary vascular endothelium (PVEC). We will add female and male sex hormones at physiological concentrations to more accurately model biological sex differences in the cellular microenvironment. We will conduct biochemical analysis of cellular injury, viral load, and inflammatory status to correlate with single-cell transcriptomic analysis (scRNAseq)of airway epithelial and myeloid responses to SARS-CoV2 infection in the model. Target identification experiments will determine if sex hormones (E2 and P4) or the cell autonomous effects of sex chromosomes attenuate viral load and inflammatory responses in the female model. These investigations will yield a robust dataset combining assessment of tissue-level injury responses with single cell epithelial and myeloid transcriptomic responses that will inform our current understanding of male and female responses to SARS-CoV2 infection. Our data will provide actionable information regarding continued investigation of female sex hormone therapy as a novel treatment for COVID-19 and other forms of acute respiratory distress and inflammatory crisis. More broadly, this work will establish methods for the creation of representative female and male microphysiological systems that will translate to other organ and disease modeling applications.
More about Mark J. Mondrinos, PhD >> (https://sse.tulane.edu/bme/faculty/mark-mondrinos)

Question 2

Acute Estradiol and Progesterone Therapy in Hospitalized Adults to Reduce COVID-19 Severity: A Randomized Control Trial - Dragana Lovre, MD

Accepted Answer

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Coronavirus SARS-CoV-2, causing COVID-19, has killed over 2.8 million  people globally, including 550,000 in the US as of March 2021. Apart  from corticosteroids, most available therapeutic options are at best  marginally efficient in reducing disease severity and mortality and  extremely expensive. Therefore, the systematic investigation of  clinically approved drugs is a priority in order to determine what does  improve the disease. Our current understanding of the disease is that  COVID-19 deaths result from an inappropriate immune response leading to  cytokine storm and resulting in multiorgan failure.  Men with COVID-19  have a uniformly more severe outcome than women. It is established that  women exhibit heightened immune responses to viral infections compared  to men and that the main female steroids (17β-estradiol and  progesterone) exhibit potent immuno-modulatory and anti-inflammatory  actions. We hypothesize that a short treatment with the combination of  well-studied, widely available and inexpensive estradiol (E2) and  progesterone (P4) administered early and as a prevention in addition to  standard of care (SOC), will prevent or mitigate the cytokine storm  while increasing antibody production and prevent severe outcomes. This  study aims to determine to what extent a short systemic E2P4 therapy,  administered early to hospitalize and confirmed COVID-19 positive  patients of both sexes in addition to SOC can reduce the severity of  symptoms and outcomes compared to SOC alone. 120 patients will be  enrolled in a 1:1 ratio of 5 day treatment with drug and placebo.  Clinical status will be assessed at day 14 and day 28 and 60 with  primary outcome of clinical improvement from moderate disease to mild  disease on the 9-point World Health Organization ordinal scale.  The  study has been reviewed by the FDA and granted IND#152499. 
More about Dragana Lovre, MD >> (https://medicine.tulane.edu/departments/medicine-endocrinology-metabolism/faculty/dragana-lovre-md)

Question 3

Sex Differences in COVID-19 Outcomes: Role of Sex Hormones, Inflammation, Comorbidities, and Socio-demographics 
Yilin Yoshida, PhD

Accepted Answer

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Adult men of all ages are at higher risk of severe illness and death  from coronavirus disease 2019 (COVID-19) compared to women. Sex  differences in COVID-19 epidemiology are insufficiently understood. The  lower mortality from COVID-19 in women may be due to the protective and  immunomodulatory actions of female sex hormones. Post-menopausal women  with COVID-19 may be at higher risk for adverse outcomes compared to  those who were pre-menopausal. Moreover, menopause hormone therapy may  protect against COVID-19 severe outcomes. Additionally, inflammatory  biomarkers are likely to be associated with sex heterogeneity in  COVID-19 severe outcomes. In previous studies, men were more likely to  exhibit systemic inflammation compared to women, with increased  procalcitonin, ferritin, a neutrophil-to-lymphocyte ratio (NLR) >6,  and a greater percentage of monocytes. In our study of hospitalized  COVID-19 patients in New Orleans, we found that increased NLR and  ferritin were independent determinants of mortality in women only. In  contrast, elevated D-dimer, a marker of hypercoagulability, was an  independent predictor of severe outcomes or death in men, but not in  women. Further, comorbidities, such as hypertension, diabetes, chronic  pulmonary disease, and cardiovascular disease, associated with poor  prognosis of COVID-19 are also known to produce higher mortality in men.  Therefore, underlying comorbidities could contribute to the male-biased  mortality from COVID-19. Finally, risk factors for COVID-19 outcomes  may differ by sex across races/ethnicities and regions. The specific  aims of this study are to:

1. Determine if pre-menopausal status and menopausal hormone therapy are protective against COVID-19 severe outcomes
2. Determine the sex-specific role of inflammatory biomarkers as determinants of COVID-19 severe outcomes
3. Determine the sex-specific role of comorbidities alone or in combination in COVID-19 severe outcomes
4. Assess the socio-demographic variations of sex difference in these associations.
 					  
This study will leverage the population-based datasets such as  the Viral Infection and Respiratory Illness Universal Study (VIRUS) and  the National COVID Cohort Collaborative (N3C) data, to examine COVID-19  epidemiology in a sex-specific manner. This analysis is expected to  provide a new understanding of the biological, clinical, and social  determinants of COVID-19 severity and the role of sex in COVID-19  outcomes across races/ethnicities and regions.

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