Initial immune response after exposure to Mycobacterium tuberculosis or to SARS-COV-2: similarities and differences

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) and Coronavirus disease-2019 (COVID-19), whose etiologic agent is severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), are currently the two deadliest infectious diseases in humans, which together have caused about more than 11 million deaths worldwide in the past 3 years. TB and COVID-19 share several aspects including the droplet- and aerosol-borne transmissibility, the lungs as primary target, some symptoms, and diagnostic tools. However, these two infectious diseases differ in other aspects as their incubation period, immune cells involved, persistence and the immunopathological response. In this review, we highlight the similarities and differences between TB and COVID-19 focusing on the innate and adaptive immune response induced after the exposure to Mtb and SARS-CoV-2 and the pathological pathways linking the two infections. Moreover, we provide a brief overview of the immune response in case of TB-COVID-19 co-infection highlighting the similarities and differences of each individual infection. A comprehensive understanding of the immune response involved in TB and COVID-19 is of utmost importance for the design of effective therapeutic strategies and vaccines for both diseases.

Keywords: COVID-19; M. tuberculosis; SARS-CoV-2; T cell response; antibody response; co-infection; innate response; tuberculosis.

Figure 1

Kinetic of the immune response to SARS-CoV-2 and Mtb. (A) SARS-CoV-2 infection evolves rapidly. The innate immune response occurs after about 3 days and is detectable through immunoenzymatic assays and flow cytometry. The antigen-specific T cell response appears around 5-7 days concurrently also with the onset of symptoms, whereas the antibody response appears later around 8-12 days. The adaptive immune response is detectable by immunoenzymatic assays, flow cytometry and IGRA. (B) Mtb causes a slow-progressing infection that might result in the development of TB disease even after many years. The innate immune response occurs after about 2 weeks and is detectable through immunoenzymatic assays and flow cytometry as for SARS-CoV-2. The antigen-specific T cell response is detectable around 4-6 weeks by means IGRA, TST, immunoenzymatic assays and flow cytometry. SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; Mtb, Mycobacterium tuberculosis; IFNs, interferons; DCs, dendritic cells; NK, natural killer; Tfh, T follicular helper lymphocytes; Th, T helper; IGRA, IFN-γ release assay; TST, tuberculin skin test. Created with BioRender.com.

Figure 2

Initial immune response after exposure to SARS-CoV-2 and Mtb. Both SARS-CoV-2 and M. tuberculosis (Mtb) are transmitted by aerosols or droplets. SARS-CoV-2 infection (1): virions enter into the airways and (2), once arrived in the lung, infect epithelial lung cells via recognition and binding of the spike protein to the ACE2 cell receptor. (3) Viral RNA, once released inside the cells, is recognized by endosomal (TLR3, TLR7) or cytosolic (RIG-I) receptors and activate downstream signaling pathways (NF-kB and IRFs) (4) leading to the release of IFNs, pro-inflammatory cytokines and chemokines favoring immune cell recruitment, including neutrophils and DCs. (5) Infected DCs migrate to the lymph nodes for T and B cell priming. (6) Primed T cells and plasma cells go back to the infection site via blood where they exert their functions, including apoptosis induced by cytotoxic T cells and viral neutralization. Mtb infection: (1) Mtb bacilli enter into the airways and (2) are phagocytosed by alveolar macrophages. (3) Alveolar macrophages migrate to lung interstitium, where they form aggregates and (4) release cytokines promoting the recruitment of immune cells, such neutrophils, macrophages and DCs. (5) Infected DCs migrate to lymph nodes to prime T cells that are recruited at the infection sites where they contribute to the formation of the organized granuloma. SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; Mtb, Mycobacterium tuberculosis; ACE2, angiotensin-converting enzyme 2; TMPRSS2, type 2 transmembrane serine protease; TLR, toll-like receptor; IFNs, interferons; RIG, retinoic acid-inducible gene-I; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; IRFs, interferon regulatory factors; DCs, dendritic cells; NK, natural killer; Tfh, T follicular helper lymphocytes; Th, T helper. Created with BioRender.com.

Figure 3

Comparison of the immune response in SARS-CoV-2, Mtb or Mtb/SARS-CoV-2 infection. The innate immune response induced after exposure to SARS-CoV-2 or Mtb is characterized by the production of pro-inflammatory cytokines including IL-1β and TNF-α. In Mtb/SARS-CoV-2 co-infection there is an overproduction of pro-inflammatory cytokines. SARS-CoV-2 infection presents also an early type I IFN production, which is absent or delayed in severe COVID-19 patients. SARS-CoV-2 infection is also characterized by a higher neutrophil count, whereas a higher monocyte/lymphocyte ratio is observed in Mtb-infected patients. Both SARS-CoV-2 and Mtb infected subjects show lymphocytopenia and T cell activation, which are even more prominent in case of co-infection. In co-infected individuals a major impairment of antigen-specific response to Mtb and SARS-CoV-2, and granuloma disruption is present. SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; Mtb, Mycobacterium tuberculosis; IFNs, interferons; DCs, dendritic cells; NK, natural killer; Th, T helper; Ig, immunoglobulin. Created with BioRender.com.