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      Pathology of TB/COVID-19 Co-Infection: The phantom menace

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          Abstract

          Despite the high number of victims of COVID-19, tuberculosis (TB) remains as the leading cause of death among infectious diseases worldwide. Since the beginning of the pandemic, there is an increasing number of studies trying to elucidate the interactions between Mycobacterium tuberculosis and SARS-CoV-2. The first case reports point to a worsening of respiratory symptoms in co-infected TB/COVID-19 individuals. However, data from the cohort studies has shown some conflicting results. This study proposes to conduct a systematic review on the current literature on TB/COVID-19 co-infection cohorts, evaluating clinical and epidemiological data, focusing on its implications to the immune system. From an immunological perspective, the TB/COVID-19 co-infection has the potential to generate a "perfect storm". The disorders induced by each pathogen to the immune modulation tend to induce an unbalanced inflammatory response, which can promote the progression and worsening of both diseases. Understanding the nature of the interactions between M. tuberculosis and SARS-CoV-2 will be crucial for the development of therapeutic strategies against co-infection.

          Highlights

          • Some of the countries most affected by the COVID-19 pandemic also present the highest global incidences of tuberculosis.

          • Tuberculosis and COVID-19 have similar clinical characteristics, compromising its diagnosis and worsening both infections prognosis.

          • Many of the damages and complications of COVID-19 result from an exacerbated inflammatory response to the virus, characterized by cytokine storms and cellular infiltration in the lungs.

          • The disorders induced by each pathogen to the immune modulation tend to induce an unbalanced inflammatory response, which can promote the progression and worsening of both diseases.

          • The tuberculosis/COVID-19 co-infection tends to generate self-sustaining pro-inflammatory feedback, which contributes to the development of pulmonary complications.

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          Most cited references 67

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          SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues

          Summary There is pressing urgency to understand the pathogenesis of the severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2), which causes the disease COVID-19. SARS-CoV-2 spike (S) protein binds angiotensin-converting enzyme 2 (ACE2), and in concert with host proteases, principally transmembrane serine protease 2 (TMPRSS2), promotes cellular entry. The cell subsets targeted by SARS-CoV-2 in host tissues and the factors that regulate ACE2 expression remain unknown. Here, we leverage human, non-human primate, and mouse single-cell RNA-sequencing (scRNA-seq) datasets across health and disease to uncover putative targets of SARS-CoV-2 among tissue-resident cell subsets. We identify ACE2 and TMPRSS2 co-expressing cells within lung type II pneumocytes, ileal absorptive enterocytes, and nasal goblet secretory cells. Strikingly, we discovered that ACE2 is a human interferon-stimulated gene (ISG) in vitro using airway epithelial cells and extend our findings to in vivo viral infections. Our data suggest that SARS-CoV-2 could exploit species-specific interferon-driven upregulation of ACE2, a tissue-protective mediator during lung injury, to enhance infection.
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            Reduction and Functional Exhaustion of T Cells in Patients With Coronavirus Disease 2019 (COVID-19)

            Background: The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed great threat to human health. T cells play a critical role in antiviral immunity but their numbers and functional state in COVID-19 patients remain largely unclear. Methods: We retrospectively reviewed the counts of T cells and serum cytokine concentration from data of 522 patients with laboratory-confirmed COVID-19 and 40 healthy controls. In addition, the expression of T cell exhaustion markers were measured in 14 COVID-19 cases. Results: The number of total T cells, CD4+ and CD8+ T cells were dramatically reduced in COVID-19 patients, especially in patients requiring Intensive Care Unit (ICU) care. Counts of total T cells, CD8+ T cells or CD4+ T cells lower than 800, 300, or 400/μL, respectively, were negatively correlated with patient survival. T cell numbers were negatively correlated to serum IL-6, IL-10, and TNF-α concentration, with patients in the disease resolution period showing reduced IL-6, IL-10, and TNF-α concentrations and restored T cell counts. T cells from COVID-19 patients had significantly higher levels of the exhausted marker PD-1. Increasing PD-1 and Tim-3 expression on T cells was seen as patients progressed from prodromal to overtly symptomatic stages. Conclusions: T cell counts are reduced significantly in COVID-19 patients, and the surviving T cells appear functionally exhausted. Non-ICU patients with total T cells counts lower than 800/μL may still require urgent intervention, even in the immediate absence of more severe symptoms due to a high risk for further deterioration in condition.
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              Functional exhaustion of antiviral lymphocytes in COVID-19 patients

              In December 2019, a novel coronavirus was first reported in Wuhan, China. 1 It was named by the World Health Organization as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is responsible for coronavirus disease 2019 (COVID-19). Up to 28 February 2020, 79,394 cases have been confirmed according to China’s National Health Commission. Outside China, the virus has spread rapidly to over 36 countries and territories. Cytotoxic lymphocytes such as cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells are necessary for the control of viral infection, and the functional exhaustion of cytotoxic lymphocytes is correlated with disease progression. 2 However, whether the cytotoxic lymphocytes in patients infected with SARS-CoV-2 become functionally exhausted has not been reported. We showed that the total number of NK and CD8+ T cells was decreased markedly in patients with SARS-CoV-2 infection. The function of NK and CD8+ T cells was exhausted with the increased expression of NKG2A in COVID-19 patients. Importantly, in patients convalescing after therapy, the number of NK and CD8+ T cells was restored with reduced expression of NKG2A. These results suggest that the functional exhaustion of cytotoxic lymphocytes is associated with SRAS-CoV-2 infection. Hence, SARS-CoV-2 infection may break down antiviral immunity at an early stage. SARS-CoV-2 has been identified as a genus β-coronavirus, and it shares 79.5% sequence homology with SARS-CoV. 3 In our cohort of 68 COVID-19 patients admitted to The First Affiliated Hospital (Hefei) and Fuyang Hospital (Fuyang), both of which are part of Anhui Medical University in China, there were 55 cases of mild disease (MD) and 13 cases of severe disease (SD). Patients were aged 11–84 years, and the median age of patients was 47.13 years. The percentage of male patients was 52.94%. Consistent with previous studies, many patients had fever (80.88%), cough (73.53%), and sputum (32.36%) upon admission. The prevalence of other symptoms (e.g., headache, diarrhea) was relatively low (Supplementary Table 1). The clinical features of patients infected with SARS-CoV-2 was consistent with those reported by Chen and colleagues. 4 Upon admission, the neutrophil count was remarkably higher in SD patients than in MD cases, whereas the lymphocyte count was significantly lower in SD cases than in MD cases. The concentration of total bilirubin, D-dimer, and lactate dehydrogenase in blood was higher in SD patients than that in MD patients. Levels of alanine aminotransferase and aspartate aminotransferase were slightly higher in SD cases than those in MD cases. Levels of albumin and hemoglobin were lower in SD patients than those in MD patients (Supplementary Table 2). Specifically, T cell and CD8+ T cell counts were decreased significantly in MD and SD patients compared with those in healthy controls (HCs). The number of T cells and CD8+ T cells was significantly lower in SD patients than that in MD cases. The counts of NK cells were reduced remarkably in SD patients compared with those in MD cases and HCs (Fig. 1a). Fig. 1 NKG2A+ cytotoxic lymphocytes are functionally exhausted in COVID-19 patients. a Absolute number of T cells, CD8+ T cells, and NK cells in the peripheral blood of healthy controls (n = 25) and patients with mild (n = 55) and severe (n = 13) infection with SARS-CoV-2. b Percentages of NKG2A+ NK cells and NKG2A+CD8+ T cells in the peripheral blood of healthy controls (n = 25) and patients infected with SARS-CoV-2 (n = 68). c Expression of intracellular CD107a, IFN-γ, IL-2, and granzyme-B in gated NK cells and CD8+ T cells and percentage of TNF-α+ NK cells in the peripheral blood of patients infected with SARS-CoV-2 and healthy controls. d Total number of T cells, CTLs, and NK cells in the peripheral blood of COVID-19 patients and convalescing patients. e Percentages of NKG2A+ NK cells and NKG2A+ CTL in the peripheral blood of COVID-19 patients and convalescing patients. Data are mean ± SEM. Unpaired/paired two-tailed Student’s t tests were conducted. p < 0.05 was considered significant. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001; N.S., not significant As an inhibitory receptor, NKG2A has been demonstrated to induce NK cell exhaustion in chronic viral infections. 5 Notably, NKG2A expression on NK and CD8+ T cells results in functional exhaustion of NK and CD8+ T cells. 6 In patients infected with SARS-CoV-2, NKG2A expression was increased significantly on NK and CD8+ T cells compared with that in HCs (Fig. 1b). Next, to identify the role of NKG2A on the function of NK and CD8+ T cells, levels of CD107a, interferon (IFN)-γ, interleukin (IL)-2, granzyme B, and tumor necrosis factor (TNF)-α were measured through staining of intracellular cytokines. We found lower percentages of CD107a+ NK, IFN-γ+ NK, IL-2+ NK, and TNF-α+ NK cells and mean fluorescence intensity (MFI) of granzyme B+ NK cells in COVID-19 patients than those in HCs. Consistent with these findings, COVID-19 patients also showed decreased percentages of CD107a+ CD8+, IFN-γ+CD8+, and IL-2+CD8+ T cells and MFI of granzyme B+CD8+ T cells, compared with those in HCs (Fig. 1c). Taken together, these results suggest the functional exhaustion of cytotoxic lymphocytes in COVID-19 patients. Hence, SARS-CoV-2 may break down antiviral immunity at an early stage. In our setting, ~94.12% of patients were administered antiviral therapy (Kaletra®). Chloroquine phosphate was used in 7.35% of patients, and the proportion of patients treated with IFN was 64.71%. In addition, 48.53% patients received antibiotic treatment (Supplementary Table 3). Comparison of the total number of cytotoxic lymphocytes (including CTLs and NK cells) after therapy was carried out. The total number of T cells and NK cells recovered in the convalescent period in four of the five patients, and the total count of CTLs was restored in the convalescent period in three of the five patients (Fig. 1d). Hence, efficacious therapy was accompanied by an increased number of T cells, CTLs, and NK cells. Importantly, the percentage of NKG2A+ NK cells was decreased in the convalescent period compared with that before treatment among five patients. Similarly, five patients showed a decreased percentage of NKG2A+ CTLs in the convalescent period (Fig. 1e). These findings suggest that downregulation of NKG2A expression may correlate with disease control in COVID-19 patients. We showed that NKG2A expression was upregulated on NK cells and CTLs in COVID-19 patients with a reduced ability to produce CD107a, IFN-γ, IL-2, granzyme B, and TNF-α. Also, the percentage of NKG2A+ cytotoxic lymphocytes was decreased in recovered patients infected with SARS-CoV-2, which strongly suggests that NKG2A expression may be correlated with functional exhaustion of cytotoxic lymphocytes and disease progression in the early stage of COVID-19. Although exhaustion of T and NK cells occurs in human chronic infection and tumorigenesis, T cell apoptosis (which is regarded as the host mechanism involved in chronic infection and cancer) also occurs in SARS-CoV infection. 7 Thus exhausted NKG2A+ cytotoxic lymphocytes may be present in COVID-19 patients. With regard to our finding that the percentage of NKG2A+ cytotoxic lymphocytes was decreased after antiviral therapy in COVID-19 patients, efficacious control of SARS-CoV-2 infection is related to reduce expression of NKG2A on cytotoxic lymphocytes. Therefore, in COVID-19 patients with severe pulmonary inflammation, SARS-CoV-2-induced NKG2A expression may be correlated with functional exhaustion of cytotoxic lymphocytes at the early stage, which may result in disease progression. Moreover, immune inhibitory “checkpoint” receptors that result in exhaustion of NK and T cells have been demonstrated in chronic infection and cancer. Importantly, checkpoint inhibitors such as anti-PD-1 and anti-TIGIT help to reinvigorate exhausted responses from T or NK cells in the context of chronic infection and cancer. 8,9 NKG2A is thought to be a novel inhibitory molecule on immune-checkpoint blockade. 10 Taken together, these data highlight the importance of improving the immune response of NK cells and CTLs and avoiding exhaustion of cytotoxic lymphocytes at the early stage of SARS-CoV-2 infection. Therefore, targeting NKG2A may prevent the functional exhaustion of cytotoxic lymphocytes and consequently contribute to virus elimination in the early stage of SRAS-CoV-2 infection. Supplementary information Supplementary Materials
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                Author and article information

                Journal
                Tuberculosis (Edinb)
                Tuberculosis (Edinb)
                Tuberculosis (Edinburgh, Scotland)
                Elsevier Ltd.
                1472-9792
                1873-281X
                17 November 2020
                17 November 2020
                Affiliations
                [a ]Graduate Program in Biosciences, Federal University of Health Sciences of Porto Alegre (UFCSPA), Porto Alegre, Brazil
                [b ]Basic Health Sciences Department, Federal University of Health Sciences of Porto Alegre (UFCSPA), Porto Alegre, Brazil
                Author notes
                []Corresponding author. Basic Health Sciences Department, Federal University of Health Sciences of Porto Alegre, Sarmento Leite, 245/403, Porto Alegre, RS, Brazil.
                Article
                S1472-9792(20)30187-6 102020
                10.1016/j.tube.2020.102020
                7669479
                © 2020 Elsevier Ltd. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                Categories
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                Respiratory medicine

                tuberculosis, covid-19, inflammation, immunopathology, cytokines

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