Sex differences in the susceptibility and response to SARS-CoV-2 infection

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A new study led by researchers from Cedars-Sinai Medical Center, California-USA has confirmed all preliminary findings and hypothesis that SARS-CoV-2 infections irrespective of even mild or asymptomatic will trigger autoantibodies leading to variety autoimmune issues in the human host.

The study findings were published in the peer reviewed Journal of Translational Medicine.
 https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-021-03184-8

Mechanisms underlying sex differences in both susceptibility and response to SARS-CoV-2 infection remain poorly understood. Biological sex differences have become manifest with respect to vulnerability to infection, adaptive immune responses, and the equilibrium of inflammation and tissue repair in the resolution of infection [1].

Recent evidence points to the possible contributions of triggering and persistence of autoimmune activation in SARS-CoV-2-infected COVID-19 patients [2, 3]. Intriguingly, despite classic autoimmune diseases being more prevalent in females, emerging studies have revealed a paradoxical male predominance of autoimmune activation in the setting of severe COVID-19 illness [4].

The extent to which such paradoxical sex differences in triggered autoimmunity may exist and persist across the broader clinical spectrum of SARS-CoV-2 infection is unclear.

Recognizing that sex bias is potentially introduced when assessing autoimmune activation in the setting of more severe forms of COVID-19 illness, we deliberately aimed to interrogate sex-specific autoimmune activation after SARS-CoV-2 exposure in the absence of any extreme manifestations of clinical disease.

Therefore, using an array to detect autoantibodies (AABs) to 91 antigens previously linked to a range of classic autoimmune diseases, we sought to comprehensively examine the diversity of AAB responses in male and female health care workers (HCWs) who were exposed to SARS-CoV-2 and self-reported presence or absence of distinct symptoms associated with COVID-19.

Importantly retrospective symptoms were correlated with autoimmune response to ascertain potential prevalence of long-lasting symptoms driven by host autoimmune response.

Results

The primary study cohort included HCW participants identified as prior SARS-CoV-2 infected individuals based on a positive anti-N IgG index. The comparator study cohorts included 53 HCs and 6 SLE patients. The demographic, clinical, exposure and symptom response characteristics of the study sample are shown in Additional file 1: Table S2.

The primary cohort of N = 177 HCWs had a mean age of 35 [IQR: 30–44] years and included 65% women, 68% of non-white race, and 28% of Hispanic/Latinx ethnicity.

For this cohort, we graded severity of prior SARS-CoV-2 infection based on reported symptoms burden (based on up to 21 distinct possible symptoms) and timing (0 to 6 months prior to assessment and assays). We categorized HCWs based on the number of reported symptoms with into three groups, asymptomatic with no symptoms reported (N = 23), mildly symptomatic with 1 to 7 symptoms reported (N = 64) and more than mildly symptomatic (N = 90) with more than 7 symptoms reported. Rates of sex-specific positivity for the AABs detected were not significantly different between the HCW cases and HC controls.

Among the HCW cases, males demonstrated an overall broader and more diverse elevation in AAB levels than females, particularly in relation to greater symptom burden. Among asymptomatic individuals, AAB reactivity to 25 out of 91 antigens (28%) was detected in men, whereas AAB reactivity to 66 out of 91 antigens (72%) was reported in women. By contrast, among individuals with mild symptoms, 58 out of 91 antigens (64%) showed positive reactivity in men versus 33 out of 91 (36%) in women. Among individuals with more than mild symptoms (N = 90), AABs to 75 out of 91 antigens (82%) showed positive reactivity in men versus only 16 out of 91 antigens (18%) in women.

Sex‐specific frequency of symptoms

As shown in Fig. 1, the vast majority of symptoms related to prior SARS-CoV-2 infection were experienced similarly by men and women. Although specific symptoms appeared to be reported more frequently by men (e.g., chills, fever, shortness of breath, diarrhea, conjunctivitis) and other symptoms were reported more frequently by women (e.g., loss of appetite, nausea, and productive cough), these differences were not statistically significant (Additional file 1: Table S2).

Similar to the specific types of symptoms assessed, we observed that varying degrees of total symptom burden were also distributed relatively equally between the sexes (Fig. 1). There was also no significant difference between females and males and timing of the reported symptoms.

In co-occurrence analyses, we found among 21 total symptoms that co-occurrence of symptoms was significant for 137 symptom pairs in women compared to 91 symptom pairs in men (Additional file 1: Fig. S1). Notably the most frequently co-occurring symptoms in women (chest pain, productive cough, chills, headache, fever) were similar to those in men (chest pain, fever, headache, chills, nasal congestion, dry cough). Chest pain was the single most frequently co-occurring symptom in both sexes, and significantly paired with occurrence of 17 other symptoms in women and 10 other symptoms in men.

figure1
Sex-specific frequency of symptoms type and overall symptoms burden, in men and women previously infected by SARS-CoV-2. In our primary study cohort, the distribution of experienced symptoms was generally similar between men and women (A) with some exceptions including certain distinct symptoms being more frequent in men (e.g., chills, fever, conjunctivitis) and other distinct symptoms being more frequent in women (e.g., loss of appetite, nausea). In analyses of overall symptom burden, frequencies of asymptomatic, mildly symptomatic, and more than mildly symptomatic persons were relatively equally distributed between the sexes (B)

Sex‐specific frequency of autoantibody response

In age-adjusted regression analyses, we examined the association of sex (female versus male) with measured plasma levels for each of the 91 AABs assayed. Across the entire cohort, the majority of assayed AABs were associated with male sex and the minority with female sex but the sex-specific frequency and magnitudes of association varied by symptom burden (Fig. 2).

Among asymptomatic individuals, the breadth and magnitude of AAB reactivity was much more pronounced in females compared to males (Fig. 2B). Notably, AABs to cytokine and chemokine antigens (IL6 and CSF2) involved in immune defense, together with lung specific proteins (gastrin release peptide (GRP) and serpin family B member 3 (SERPINB3), were predominantly elevated in asymptomatic females.

By contrast, thyroid stimulating hormone receptor (TSHR) and lysine demethylase 6B (KDM6B), which are known primary antigens in autoimmune diseases, including Graves’ disease and Hashimoto’s disease [13] and systemic sclerosis (SS also termed scleroderma) [14] were highly expressed in asymptomatic males.

Among all participants who had at least mild symptoms, the range and degree of AAB reactivity was more pronounced in males compared to females (Fig. 2C, D). The most abundant AABs in males were preferentially enriched in classical nuclear AABs such as small nuclear ribonucleoprotein polypeptide C (SNRPC) a target of autoreactive B cells and T cells in several rheumatic diseases including SLE, mixed connective tissue disease (MCTD) [15], inflammatory myositis, and SS [16]; nuclear mitotic apparatus protein 1 (NUMA1), antibody associated with SLE, SS, and RA [17]; and autoantibodies recognizing dihydrolipoamide succinyltransferase (DLST) found in primary biliary cirrhosis [18]. In this group, the highest expressed antibody was Moloney leukemia virus 10 homolog (MOV10), a putative RNA which inhibits replication of a number of retroviruses [19, 20] and recently showed to interacts with SARS-CoV-2 proteins [21].

figure2
Sex associations with autoantibody activation by symptoms burden, in men and women previously infected by SARS-CoV-2. The age-adjusted associations of sex (female versus male) with AABs activation across the panel of 91 antigens are shown for the primary cohort overall (A) and within persons with varying loads of symptom burden: asymptomatic (B), mild symptom burden (C), more than mild symptom burden (D)

In analyses repeated using AAB values normalized for both positive and negative controls, results were unchanged with primary sex-specific antigens consistently identified across the pre-specified disease severity groups including asymptomatic (i.e. TSHR and PPL in males; GRP, CSF2, and SERNIPB3 in females), mildly symptomatic (i.e. IL6, TRIM33, and MOV10 in males; LARP1, TPO, and MPO in females), and more than mildly symptomatic (i.e. MOV10, ECE1, and NUMA1 in males; LARP1 and PTPRN in females).

In sex-specific cluster analyses, we observed an overall broader distribution as well as larger number of distinct clusters of AABs in men compared to women particularly among the asymptomatic and mildly symptomatic groups (Additional file 1: Figs. S2 and S3). We also observed findings consistent with broader activation of AABs corresponding with greater symptom burden, a marker of relative illness severity, in both sexes (Additional file 1: Table S3).

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