Lucila Beuses

Introduction: Tuberculosis is the leading cause of death worldwide from an infectious disease among adults.¹ Tuberculosis is a bacterial infection caused by Mycobacterium tuberculosis (Mtb), which primarily occurs after inhalation into the respiratory tract.^{2, 3} Here, Mtb becomes internalized by alveolar macrophages and begins to manipulate host cellular trafficking, innate immune responses, and cell death pathways to ensure its survival.^{1, 2, 4} Currently, treatment consists of anti-tuberculosis drugs; however, the rise of antibiotic resistance in Mtb requires the development of new treatment options and has facilitated studies on Mtb LytR-CpsA-Psr (LCP) protein-encoding genes, Rv3267 and Rv3484.^{1, 5-8} Lcp1/CpsA1, from Rv3267 gene, has been linked to Mtb cell wall synthesis, and CpsA/CpsA2, from Rv3484 gene, has been implicated in Mtb’s ability to evade delivery to phagolysosomes^5-8. These findings could suggest new therapeutic targets for treatment of tuberculosis. Methods: Researchers utilized a cell-free functional assay to test Lcp1/CpsA1’s ability to ligate arabinogalactan to peptidoglycan in the Mtb cell wall.⁵ To test the essentiality of Lcp1/CpsA1, researchers used a conditional expression specialized transduction essentiality test (CESTET)⁵. Researchers generated a Mtb CpsA/CpsA2 mutant and examined differences in cell wall properties to determine this protein’s role in cell wall synthesis.⁶ To study the essentiality of CpsA/CpsA2, researchers performed in vivo characterization of an Rv3484 deletion mutant of Mtb in the lungs.⁸ Researchers also compared the survivability of wildtype Mtb with mutant CpsA/CpsA2 Mtb in wildtype macrophages versus Nox2 knockout macrophages.⁶ To study age-dependent factors of Mtb infection, alveolar macrophages from healthy infants and adults were obtained and incubated with live virulent Mtb.⁹ Results: Studies indicate that Lcp1/CpsA1 ligates arabinogalactan to peptidoglycan.⁵ CESTET showed that Lcp1/CpsA1 is critical for Mycobacteria cell wall integrity and viability.⁵ Studies suggest that CpsA/CpsA2 does not play a significant role in Mtb cell wall synthesis.⁶ However, Rv3484 gene was shown to be essential for Mtb viability.⁸ CpsA/CpsA2 was shown to inhibit CYBB recruitment and subsequent LC3-associated phagocytosis (LAP).⁶ Studies suggest infant alveolar macrophages are more vulnerable to Mtb infection due to decreased expression of CYBB gene and genes involved in antimycobacterial phagosome maturation.⁹ Conclusions: Studies have found that inhibition of Lcp1/CpsA1 (Rv3267 gene) leads to disruption of Mtb cell wall synthesis and integrity. Additionally, inhibition of CpsA/CpsA2 (Rv3484 gene) leads to disinhibition of CYBB recruitment and LAP, resulting in destruction of Mtb by phagolysosomes. Consideration of LCP protein-encoding genes as targets could lead to new effective therapies against tuberculosis.

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