Do sex-specific immunobiological factors and differences in angiotensin converting enzyme 2 (ACE2) expression explain increased severity and mortality of COVID-19 in males?

Jens Vikse 1 , Giuseppe Lippi 2  and Brandon Michael Henry 3
  • 1 Clinical Immunology Unit, Stavanger University Hospital, Stavanger, Norway
  • 2 Section of Clinical Biochemistry, University of Verona, Verona, Italy
  • 3 Cardiac Intensive Care Unit, The Heart Institute, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave., Cincinnati, USA
Jens Vikse, Giuseppe Lippi and Brandon Michael Henry
  • Corresponding author
  • Cardiac Intensive Care Unit, The Heart Institute, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH, 45229, USA
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Abstract

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2), shares similarities with the former SARS outbreak, which was caused by SARS-CoV-1. SARS was characterized by severe lung injury due to virus-induced cytopathic effects and dysregulated hyperinflammatory state. COVID-19 has a higher mortality rate in men both inside and outside China. In this opinion paper, we describe how sex-specific immunobiological factors and differences in angiotensin converting enzyme 2 (ACE2) expression may explain the increased severity and mortality of COVID-19 in males. We highlight that immunomodulatory treatment must be tailored to the underlying immunobiology at different stages of disease. Moreover, by investigating sex-based immunobiological differences, we may enhance our understanding of COVID-19 pathophysiology and facilitate improved immunomodulatory strategies.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2), shares similarities with the former SARS outbreak, which was caused by SARS-CoV-1. [1] SARS was characterized by severe lung injury due to virus-induced cytopathic effects and dysregulated hyperinflammatory state [2]. COVID-19 has a higher mortality rate in men both inside and outside China. [3], [4] This has been attributed to sex differences in comorbidities, smoking, cultural and psychosocial gender factors. [5] However, sex-specific immunobiological differences may also be involved, which may influence efficacy of COVID-19 immunomodulatory therapies.

RNA viruses like SARS-CoV-2 can be recognized by endosomal Toll-like receptor (TLR) 3 and TLR7, leading to production of type I interferons (IFN-α and IFN-β) which suppress viral replication and augment the host antiviral response. [6] SARS-CoV-1 inhibits proteins involved in TLR3 and TLR7 signaling pathways, [7], [8] thereby attenuating type I IFN response. In mice models, timing of type I IFN-response impacted SARS-CoV-1 disease severity. [2] Pretreatment of IFN-α inhibited SARS-CoV-1 replication in vivo, and an early type I IFN response (through administration of recombinant IFN-β 6 h post infection) protected mice from clinical lung disease. [2], [9] On the contrary, delayed and persistent type I IFN-response was associated with dysregulated hyperinflammatory state and severe lung disease characterized by excessive pulmonary inflammation, alveolar edema, increased pro-inflammatory cytokines (including interleukin-6) and enhanced T-cell apoptosis. [2]

The TLR7 gene is located on X chromosome, escapes X chromosome inactivation and has higher expression in females. [10] TLR7 ligands induce greater release of IFN-α from peripheral blood mononuclear cells from females in vitro. [11] Furthermore, female sex hormones have immunomodulatory effects. [12] Estradiol augment TLR7-induced type I IFN-response, [13] and SARS-CoV-1 had higher mortality in gonadectomized female mice compared to non-gonadectomized female counterparts. [14]

Additionally, females have higher CD4+ lymphocyte counts, [12] a subtype of blood cells essential for maintaining an effective and balanced immune response, with loss of CD4+ cells resulting in potentially increased immune-mediated pneumonitis and delayed viral clearance. [15] SARS-CoV-2 infection results in significant lymphopenia, which is associated with higher mortality. [16] Greater CD4+ lymphocyte reserve may potentially decrease the risk of severe COVID-19 in women.

Finally, alterations in tissue expression of primary host receptor for SARS-CoV-2, angiotensin converting enzyme 2 (ACE2), may play a role in these sex differences. In three different RNA expression databases, (Human Protein Atlas, FAMTOM5 and GETx), ACE2 was found to be highly expressed in testicular cells at the protein levels, while little ACE2 expression was seen in ovarian tissue. [17] Evidence of COVID-19 infection of testicles is suggested by reported significant alterations in testosterone to luteinizing hormone (T to LH) ratio, with a low ratio in those infected with the virus (0.74) as compared to healthy controls (1.31). [18] Moreover, autopsy reports from SARS-CoV-1 demonstrated orchitis. [19] Importantly, the testes are a site of immune privilege, protected by the blood-testes barrier. As such, we proffer that the high ACE2 expression combined with immune privilege that limit T lymphocyte destruction of virally infected cells, may enable testes to serve as viral reservoir for COVID-19, leading to delayed viral clearance, potentially higher viral loads, and prolonged accumulative lung and systemic tissue damage.

We hypothesize that sex-specific immunobiological differences, including timing of type I IFN-response, may contribute at least in part to the observed sex differences in COVID-19 severity and mortality. Clinical trials using IFN-α are currently underway. We advise caution as type I IFN response may be dynamic and pleiotropic. Immunomodulatory treatment must be tailored to the underlying immunobiology at different stages of disease. Investigating sex-based immunobiological differences may enhance our understanding of COVID-19 pathophysiology and facilitate improved immunomodulatory strategies.

Research funding: None declared.

Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

Competing interests: Authors state no conflict of interest.

References

  • 1.

    Wilder-Smith A, Chiew CJ, Lee VJ. Can we contain the COVID-19 outbreak with the same measures as for SARS?. Lancet Infect Dis 2020;20:E102–7. https://doi.org/10.1016/S1473-3099(20)30129-8.

  • 2.

    Channappanavar R, Fehr AR, Vijay R, Mack M, Zhao J, Meyerholz DK, et al. Dysregulated type I interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in SARS-CoV-infected mice. Cell Host Microbe 2016;19:181–93. https://doi.org/10.1016/j.chom.2016.01.007.

  • 3.

    The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team. The epidemiological characteristics of an outbreak of 2019 novel coronavirus disease (COVID-19). China CDC Weekly 2020;2:113–22. https://doi.org/10.46234/ccdcw2020.032.

  • 4.

    Italian National Institute of Health–Istituto Superiore di Sanità. Report on the characteristics of COVID-19 positive patients deceased in Italy. Last update, March 20; 2020.

  • 5.

    Wenham C, Smith J, Morgan R. COVID-19: the gendered impacts of the outbreak. Lancet 2020;395:846–8. https://doi.org/10.1016/s0140-6736(20)30526-2.

  • 6.

    Wang BX, Fish EN. Global virus outbreaks: interferons as 1st responders. Semin Immunol 2019;43:101300. https://doi.org/10.1016/j.smim.2019.101300.

  • 7.

    Li SW, Wang CY, Jou YJ, Huang SH, Hsiao LH, Wan L, et al. SARS coronavirus papain-like protease inhibits the TLR7 signaling pathway through removing Lys63-linked polyubiquitination of TRAF3 and TRAF6. Int J Mol Sci 2016;17:678. https://doi.org/10.3390/ijms17050678.

  • 8.

    Siu KL, Kok KH, Ng MH, Poon VK, Yuen KY, Zheng BJ, et al. Severe acute respiratory syndrome coronavirus M protein inhibits type I interferon production by impeding the formation of TRAF3.TANK.TBK1/IKKepsilon complex. J Biol Chem 2009;284:16202–9. https://doi.org/10.1074/jbc.m109.008227.

  • 9.

    Barnard DL, Day CW, Bailey K, Heiner M, Montogomery R, Lauridsen L, et al. Evaluation of immunomodulators, interferons and known in vitro SARS-CoV inhibitors for inhibition of SARS-CoV replication in BALB/c mice. Antiviral Chem Chemother 2006;17:275–84. https://doi.org/10.1177/095632020601700505.

  • 10.

    Souyris M, Cenac C, Azar P, Daviaud D, Canivet A, Grunewald S, et al. TLR7 escapes X chromosome inactivation in immune cells. Sci Immunol 2018;3:eaap8855. https://doi.org/10.1126/sciimmunol.aap8855.

  • 11.

    Berghöfer B, Frommer T, Haley G, Fink L, Bein G, Hackstein H. TLR7 ligands induce higher IFN-alpha production in females. J Immunol 2006;177:2088–96. https://doi.org/10.4049/jimmunol.177.4.2088.

  • 12.

    Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol 2016;16:626–38. https://doi.org/10.1038/nri.2016.90.

  • 13.

    Seillet C, Laffont S, Trémollières F, Rouqie N, Ribot C, Arnal JF, et al. The TLR-mediated response of plasmacytoid dendritic cells is positively regulated by estradiol in vivo through cell-intrinsic estrogen receptor α signaling. Blood 2012;119:454–64. https://doi.org/10.1182/blood-2011-08-371831.

  • 14.

    Channappanavar R, Fett C, Mack M, Ten eyck PP, Meyerholz DK, Perlman S. Sex-based differences in susceptibility to severe acute respiratory syndrome coronavirus infection. J Immunol 2017;198:4046–53. https://doi.org/10.4049/jimmunol.1601896.

  • 15.

    Chen J, Lau YF, Lamirande EW, Paddoock CD, Bartless JH, Zaki SR, et al. Cellular immune responses to severe acute respiratory syndrome coronavirus (SARS-CoV) infection in senescent BALB/c mice: CD4+ T cells are important in control of SARS-CoV infection. J Virol 2010;84:1289–301. https://doi.org/10.1128/jvi.01281-09.

  • 16.

    Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan. China. Intensive Care Med; 2020.

  • 17.

    Shastri A, Wheat J, Agrawal S, Chaterjee N, Pradham K, Goldfinger M. Delayed clearance of SARS-CoV2 in male compared to female patients: high ACE2 expression in testes suggests possible existence of gender-specific viral reservoirs. Preprint at medRxiv 2020. https://doi.org/10.1101/2020.04.16.20060566.

  • 18.

    Ma L, Xie W, Li D, Shi L, Mao Y, Xiong Y, et al. Effect of SARS-CoV-2 infection upon male gonadal function: a single center-based study. Preprint at medRxiv 2020. https://doi.org/10.1101/2020.03.21.20037267 (2020).

  • 19.

    Xu J, Qi L, Chi X, Yang J, Wei X, Gong E, et al. Orchitis: a complication of severe acute respiratory syndrome (SARS). Biol Reprod 2006 2016:74:410–16. https://doi.org/10.1095/biolreprod.105.044776.

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  • 1.

    Wilder-Smith A, Chiew CJ, Lee VJ. Can we contain the COVID-19 outbreak with the same measures as for SARS?. Lancet Infect Dis 2020;20:E102–7. https://doi.org/10.1016/S1473-3099(20)30129-8.

  • 2.

    Channappanavar R, Fehr AR, Vijay R, Mack M, Zhao J, Meyerholz DK, et al. Dysregulated type I interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in SARS-CoV-infected mice. Cell Host Microbe 2016;19:181–93. https://doi.org/10.1016/j.chom.2016.01.007.

  • 3.

    The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team. The epidemiological characteristics of an outbreak of 2019 novel coronavirus disease (COVID-19). China CDC Weekly 2020;2:113–22. https://doi.org/10.46234/ccdcw2020.032.

  • 4.

    Italian National Institute of Health–Istituto Superiore di Sanità. Report on the characteristics of COVID-19 positive patients deceased in Italy. Last update, March 20; 2020.

  • 5.

    Wenham C, Smith J, Morgan R. COVID-19: the gendered impacts of the outbreak. Lancet 2020;395:846–8. https://doi.org/10.1016/s0140-6736(20)30526-2.

  • 6.

    Wang BX, Fish EN. Global virus outbreaks: interferons as 1st responders. Semin Immunol 2019;43:101300. https://doi.org/10.1016/j.smim.2019.101300.

  • 7.

    Li SW, Wang CY, Jou YJ, Huang SH, Hsiao LH, Wan L, et al. SARS coronavirus papain-like protease inhibits the TLR7 signaling pathway through removing Lys63-linked polyubiquitination of TRAF3 and TRAF6. Int J Mol Sci 2016;17:678. https://doi.org/10.3390/ijms17050678.

  • 8.

    Siu KL, Kok KH, Ng MH, Poon VK, Yuen KY, Zheng BJ, et al. Severe acute respiratory syndrome coronavirus M protein inhibits type I interferon production by impeding the formation of TRAF3.TANK.TBK1/IKKepsilon complex. J Biol Chem 2009;284:16202–9. https://doi.org/10.1074/jbc.m109.008227.

  • 9.

    Barnard DL, Day CW, Bailey K, Heiner M, Montogomery R, Lauridsen L, et al. Evaluation of immunomodulators, interferons and known in vitro SARS-CoV inhibitors for inhibition of SARS-CoV replication in BALB/c mice. Antiviral Chem Chemother 2006;17:275–84. https://doi.org/10.1177/095632020601700505.

  • 10.

    Souyris M, Cenac C, Azar P, Daviaud D, Canivet A, Grunewald S, et al. TLR7 escapes X chromosome inactivation in immune cells. Sci Immunol 2018;3:eaap8855. https://doi.org/10.1126/sciimmunol.aap8855.

  • 11.

    Berghöfer B, Frommer T, Haley G, Fink L, Bein G, Hackstein H. TLR7 ligands induce higher IFN-alpha production in females. J Immunol 2006;177:2088–96. https://doi.org/10.4049/jimmunol.177.4.2088.

  • 12.

    Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol 2016;16:626–38. https://doi.org/10.1038/nri.2016.90.

  • 13.

    Seillet C, Laffont S, Trémollières F, Rouqie N, Ribot C, Arnal JF, et al. The TLR-mediated response of plasmacytoid dendritic cells is positively regulated by estradiol in vivo through cell-intrinsic estrogen receptor α signaling. Blood 2012;119:454–64. https://doi.org/10.1182/blood-2011-08-371831.

  • 14.

    Channappanavar R, Fett C, Mack M, Ten eyck PP, Meyerholz DK, Perlman S. Sex-based differences in susceptibility to severe acute respiratory syndrome coronavirus infection. J Immunol 2017;198:4046–53. https://doi.org/10.4049/jimmunol.1601896.

  • 15.

    Chen J, Lau YF, Lamirande EW, Paddoock CD, Bartless JH, Zaki SR, et al. Cellular immune responses to severe acute respiratory syndrome coronavirus (SARS-CoV) infection in senescent BALB/c mice: CD4+ T cells are important in control of SARS-CoV infection. J Virol 2010;84:1289–301. https://doi.org/10.1128/jvi.01281-09.

  • 16.

    Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan. China. Intensive Care Med; 2020.

  • 17.

    Shastri A, Wheat J, Agrawal S, Chaterjee N, Pradham K, Goldfinger M. Delayed clearance of SARS-CoV2 in male compared to female patients: high ACE2 expression in testes suggests possible existence of gender-specific viral reservoirs. Preprint at medRxiv 2020. https://doi.org/10.1101/2020.04.16.20060566.

  • 18.

    Ma L, Xie W, Li D, Shi L, Mao Y, Xiong Y, et al. Effect of SARS-CoV-2 infection upon male gonadal function: a single center-based study. Preprint at medRxiv 2020. https://doi.org/10.1101/2020.03.21.20037267 (2020).

  • 19.

    Xu J, Qi L, Chi X, Yang J, Wei X, Gong E, et al. Orchitis: a complication of severe acute respiratory syndrome (SARS). Biol Reprod 2006 2016:74:410–16. https://doi.org/10.1095/biolreprod.105.044776.

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