Prior to coronavirus disease 2019 (COVID-19), tuberculosis (TB) was the worst killer among infectious diseases. The union of these two obnoxious respiratory diseases can be devastating, with severe public health implications. The COVID-19 pandemic has affected all TB-elimination programmes due to the severe burden on healthcare systems and the diversion of funds and attention towards controlling the pandemic. The emerging data show that the COVID-19 pandemic caused a marked decrease in case notifications and bacille Calmette–Guérin immunisations, ultimately promoting disease transmission and increasing the susceptible population. The similarity between the clinical characteristics of TB and COVID-19 adds to the public health complications, with evidence of immune dysregulation in both cases leading to severe consequences. Clinical evidence suggests that severe acute respiratory syndrome coronavirus 2 infection predisposes patients to TB infection or may lead to reactivation of latent disease. Similarly, underlying TB disease can worsen COVID-19. Treatment options are limited in COVID-19; therefore, using immunosuppressive and immunomodulatory regimens that can modulate the concomitant bacterial infection and interaction with anti-TB drugs requires caution. Thus, considering the synergistic impact of these two respiratory diseases, it is crucial to manage both diseases to combat the syndemic of TB and COVID-19. M. tuberculosis is a deadly human pathogen, and the emergence of COVID-19 has hampered TB control measures. Better co-infection management can prevent disease-related complications and produce favourable outcomes. https://bit.ly/3LiiV57

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COVID-19 and tuberculosis: the double whammy of respiratory pathogens

During COVID-19 pandemic, a lot of diseases suffered from a limited access to health care services, owing to the use of resources, both technical and financial, mainly directed towards such a dramatic outbreak. Among these, tuberculosis (TB) has been one of the most penalized, with a huge delay both in diagnosis and in start of treatment, with a consequential dramatic increase in morbidity and mortality. COVID-19 and tuberculosis share similar common pathogenetic pathways, and both diseases affect primarily the lungs. About the impact of TB on COVID-19 severity and mortality, data are unclear and literature reports are often conflicting. Certainly, considering the management of coinfected patients, there are pharmacokinetic interactions between several drugs used for the therapy of SARS-CoV-2 infection and the treatment of TB.

Clinical impact of COVID-19 on tuberculosis.

Role of multiple factors likely contributing to severity-mortality of COVID-19

Mycobacterium tuberculosis (M. tb) gene Rv1515c encodes a conserved hypothetical protein exclusively present within organisms of MTB complex and absent in non-pathogenic mycobacteria. In silico analysis revealed that Rv1515c contain S-adenosylmethionine binding site and methyltransferase domain. The DNA binding and DNA methyltransferase activity of Rv1515c was confirmed in vitro. Knock-in of Rv1515c in a model mycobacteria M. smegmatis (M. s_Rv1515c) resulted in remarkable physiological and morphological changes and conferred the recombinant strain with an ability to adapt to various stress conditions, including resistance to TB drugs. M. s_Rv1515c was phagocytosed at a greater rate and displayed extended intra-macrophage survival in vitro. Recombinant M. s_Rv1515c contributed to enhanced virulence by suppressing the host defense mechanisms including RNS and ROS production, and apoptotic clearance. M. s_Rv1515c, while suppressing the phagolysosomal maturation, modulated pro-inflammatory cytokine production and also inhibited antigen presentation by downregulating the expression of MHC-I/MHC-II and co-stimulatory signals CD80 and CD86. Mice infected with M. s_Rv1515c produced more Treg cells than vector control (M. s_Vc) and exhibited reduced effector T cell responses, along-with reduced expression of macrophage activation markers in the chronic phase of infection. M. s_Rv1515c was able to survive in the major organs of mice up to 7 weeks post-infection. These results indicate a crucial role of Rv1515c in M. tb pathogenesis.

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Mycobacterium tuberculosis Methyltransferase Rv1515c Can Suppress Host Defense Mechanisms by Modulating Immune Functions Utilizing a Multipronged Mechanism

Ecological studies showed that countries with national Bacillus Calmette-Guerin (BCG) vaccination programs for tuberculosis prevention reported lower incidences of severe and fatal COVID-19 than countries without such programs. Several studies have demonstrated that the BCG vaccine can induce long-term trained Immunity in bone marrow progenitor cells. In this study, we tried to evaluate the relationship between tuberculin skin test results, BCG scar, and COVID-19 outcomes among patients with confirmed COVID-19.This was a cross-sectional study. Cases included 160 patients with confirmed COVID-19 in Zahedan hospitals (southeast Iran) in 2020, selected by convenient sampling. PPD test was performed for all patients through the intradermal technique. Collected data included demographic information, underlying conditions, PPD test results, and COVID-19 outcome. Analysis was conducted utilizing ANOVA, χ2 test, and multivariate analysis (logistic regression).The univariate analysis showed a positive relationship between older age, having underlying diseases, and positive tuberculin skin test results with the outcome of COVID-19. We also found a lower frequency of BCG scar among patients with death outcomes than recovered ones. In the multivariate analysis by logistic regression through the backward method, only age and underlying diseases remained predictors of death.Tuberculin test results might be dependent on age and underlying conditions. Our study did not show relationship between BCG vaccine and mortality in COVID-19 patients. Further investigations in different settings are required to reveal the efficacy of the BCG vaccine in preventing this devastating disease. 

Relationship between Tuberculin Skin Test and COVID-19 Outcomes among Patients with COVID-19 in Zahedan, Iran.

Will bacille Calmette-Guerin immunization arrest the COVID-19 pandemic?

Dissecting the function(s) of proteins present exclusively in Mycobacterium tuberculosis (M.tb) will provide important clues regarding the role of these proteins in mycobacterial pathogenesis. Using extensive computational approaches, we shortlisted ORFs/proteins unique to M.tb among 13 different species of mycobacteria and identified a hypothetical protein Rv1509 as a 'signature protein' of M.tb. This unique protein was found to be present only in M.tb and absent in all other mycobacterial species, including BCG. In silico analysis identified numerous putative T cell and B cell epitopes in Rv1509. Initial in vitro experiments using innate immune cells demonstrated Rv1509 to be immunogenic with potential to modulate innate immune responses. Macrophages treated with Rv1509 exhibited higher activation status along with substantial release of pro-inflammatory cytokines. Besides, Rv1509 protein boosts dendritic cell maturation by increasing the expression of activation markers such as CD80, HLA-DR and decreasing DC-SIGN expression and this interaction was mediated by innate immune receptor TLR2. Further, in vivo experiments in mice demonstrated that Rv1509 protein promotes the expansion of multifunctional CD4+ and CD8+T cells and induces effector memory response along with evoking a canonical Th1 type of immune response. Rv1509 also induces substantial B cell response as revealed by increased IgG reactivity in sera of immunized animals. This allowed us to demonstrate the diagnostic efficacy of this protein in sera of human TB patients compared to the healthy controls. Taken together, our results reveal that Rv1509 signature protein has immunomodulatory functions evoking immunological memory response with possible implications in serodiagnosis and TB vaccine development.

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Jasmine Samal

Papers

Will bacille Calmette-Guerin immunization arrest the COVID-19 pandemic?

Mycobacterium tuberculosis Specific Protein Rv1509 Evokes Efficient Innate and Adaptive Immune Response Indicative of Protective Th1 Immune Signature