Rifampicin drug resistance and host immunity in tuberculosis: more than meets the eye

Abstract

Tuberculosis (TB) is the leading cause of death due to an infectious agent, with more than 1.5 million deaths attributed to TB annually worldwide. The global dissemination of drug resistance across Mycobacterium tuberculosis (Mtb) strains, causative of TB, resulted in an estimated 450 000 cases of drug-resistant (DR) TB in 2021. Dysregulated immune responses have been observed in patients with multidrug resistant (MDR) TB, but the effects of drug resistance acquisition and impact on host immunity remain obscure. In this review, we compile studies that span aspects of altered host-pathogen interactions and highlight research that explores how drug resistance and immunity might intersect. Understanding the immune processes differentially induced during DR TB would aid the development of rational therapeutics and vaccines for patients with MDR TB.

Keywords: Mycobacterium tuberculosis; altered immunity; drug-resistance; host–pathogen interactions; rifampicin.

Figure 1-. Examples of differences observed between drug sensitive and drug resistant Mtb strains.

The presence of rifampicin drug resistance mutations is associated with broad changes in bacterium physiology and function. Some changes include increased expression of DNA-damage related DNA polymerase, dnaE2[11], differences in DNA methylation patterns[12], increased expression of cell wall- and stress-related proteins[–18], and increased accumulation of long-chain cell wall lipid phthiocerol dimycocerosate (PDIM)[3,4] This figure was created using BioRender.com

Figure 2-. Comparison of reported immune responses between DS and DR TB patients.

Clinical studies comparing peripheral and tissue immune responses largely find divergent and diminished immune responses in drug resistant (DR) TB patients relative to drug susceptible (DS) TB counterparts. While elevated proportions of T helper 1 (Th1) CD4⁺ T cells producing interferon (IFN)_γ are found in the peripheral blood of DS TB patients, Th17 CD4⁺ T cells producing IL-17 and IL-22 and T regulatory (Treg) cells producing IL-10 are elevated in DR TB patients[7,55,71]. Additionally, the CD8⁺ T cells and natural killer (NK) cells from peripheral blood of DR TB patients produce less cytotoxic and lytic mediators than similar cells from DS TB patients[58,60]. In the lungs greater proportions of Arginase 1⁺ (Arg-1⁺) alveolar macrophages (AMs) are found in DR TB patients, while inducible nitric oxide synthase⁺ (iNOS⁺) AMs are found in DS TB patients[62,64]. This figure was created using BioRender.com