Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2024 Jun 6;25(11):6255.
doi: 10.3390/ijms25116255.

Host Cell Death and Modulation of Immune Response against Mycobacterium tuberculosis Infection

Annie Vu  1 , Ira Glassman  1 , Giliene Campbell  1 , Stephanie Yeganyan  1 , Jessica Nguyen  1 , Andrew Shin  1 , Vishwanath Venketaraman  1
Affiliations
Review

Host Cell Death and Modulation of Immune Response against Mycobacterium tuberculosis Infection

Annie Vu et al. Int J Mol Sci. .

Abstract

Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB), a prevalent infectious disease affecting populations worldwide. A classic trait of TB pathology is the formation of granulomas, which wall off the pathogen, via the innate and adaptive immune systems. Some key players involved include tumor necrosis factor-alpha (TNF-α), foamy macrophages, type I interferons (IFNs), and reactive oxygen species, which may also show overlap with cell death pathways. Additionally, host cell death is a primary method for combating and controlling Mtb within the body, a process which is influenced by both host and bacterial factors. These cell death modalities have distinct molecular mechanisms and pathways. Programmed cell death (PCD), encompassing apoptosis and autophagy, typically confers a protective response against Mtb by containing the bacteria within dead macrophages, facilitating their phagocytosis by uninfected or neighboring cells, whereas necrotic cell death benefits the pathogen, leading to the release of bacteria extracellularly. Apoptosis is triggered via intrinsic and extrinsic caspase-dependent pathways as well as caspase-independent pathways. Necrosis is induced via various pathways, including necroptosis, pyroptosis, and ferroptosis. Given the pivotal role of host cell death pathways in host defense against Mtb, therapeutic agents targeting cell death signaling have been investigated for TB treatment. This review provides an overview of the diverse mechanisms underlying Mtb-induced host cell death, examining their implications for host immunity. Furthermore, it discusses the potential of targeting host cell death pathways as therapeutic and preventive strategies against Mtb infection.

Keywords: Mycobacterium tuberculosis; apoptosis; autophagy; cell death; necrosis.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
CpsA protein in LC3-associated phagocytosis. In LC3-associated phagocytosis, NADPH oxidase is recruited to the phagosome. There is a subsequent recruitment of LC3 and maturation of the phagophore, followed by a fusion of the subsequent autophagosome with a lysosome containing degradative enzymes, resulting in an autolysosome. The CpsA protein of Mtb may activate PRR but will inhibit the recruitment of NADPH oxidase.
Figure 2
Figure 2
Mtb inhibition of IFN-associated receptor (IFNAR) signaling pathway, preventing nitric oxide production.
Figure 3
Figure 3
Caspase-dependent apoptosis may occur via the intrinsic or extrinsic pathway. The intrinsic pathway is triggered by internal cellular stress or by proapoptotic Bcl-2 proteins, which cause the release of factors such as cytochrome c and apoptosis-inducing factor (AIF) from the mitochondrial intermembrane space. Such factors activate caspase 9, which activates the apoptosome, which further activates caspase 3 or 7. Of note, nitric oxide (NO) is found to upregulate Bcl-2 proteins. IFN-γ-activated macrophages further upregulate nitric oxide synthase, thereby increasing NO and thus proapoptotic Bcl-2 proteins. In contrast, the extrinsic pathway is activated via death receptors, such as Fas or TNF receptor. This activates caspase 8, which further activates caspase 3 or 7. Of note, Mtb may secrete TNF-R2, which can inhibit the TNF receptor.
Figure 4
Figure 4
Antioxidant defense in Mtb via superoxide dismutase.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Zhang T., Zhang J., Wei L., Liang H., Zhang J., Shi D., Wang Z. The global, regional, and national burden of tuberculosis in 204 countries and territories, 1990–2019. J. Infect. Public Health. 2023;16:368–375. doi: 10.1016/j.jiph.2023.01.014. - DOI - PubMed
    1. World Health Organization Global Tuberculosis Report 2023. 2023. [(accessed on 12 February 2024)]. Available online: https://www.who.int/publications/i/item/9789240083851.
    1. World Health Organization Global Tuberculosis Report 2021. 2021. [(accessed on 12 February 2024)]. Available online: https://www.who.int/publications/i/item/9789240037021.
    1. Luies L., du Preez I. The Echo of Pulmonary Tuberculosis: Mechanisms of Clinical Symptoms and Other Disease-Induced Systemic Complications. Clin. Microbiol. Rev. 2020;33:10-1128. doi: 10.1128/cmr.00036-20. - DOI - PMC - PubMed
    1. Bruchfeld J., Correia-Neves M., Källenius G. Tuberculosis and HIV Coinfection. Cold Spring Harb. Perspect. Med. 2015;5:a017871. doi: 10.1101/cshperspect.a017871. - DOI - PMC - PubMed

Grants and funding

We appreciate the funding support of NIH-NHLBI (2R15HL143545-02).