Blockade of the PD-1 / PD-L1 Axis Exacerbates Chronic Nocardia Brasiliensis Infection by Disrupting Bacterial Immune Containment in BALB/c Mice.

Abstract

Background: Therapeutic blockade of the PD-1/PD-L1 axis is a key strategy in cancer immunotherapy to reverse T cell exhaustion. However, this approach carries the risk of reactivating latent pathogens in individuals with chronic infections. The role of this immune checkpoint in granulomatous infectious diseases, particularly chronic actinomycetoma, remains largely unexplored.

Methods: To investigate this, we treated BALB/c mice with established chronic Nocardia brasiliensis actinomycetoma using the PD-L1 inhibitor atezolizumab. We assessed survival, clinical progression, and histopathology, and characterized systemic versus local immune responses through cytokine analysis and flow cytometry of lymphoid organs and lesion tissue.

Results: Actinomycetoma lesions had a paucicellular lymphocyte infiltrate, yet the few CD8+ T cells present exhibited high PD-1 expression. Atezolizumab treatment was associated with increased mortality, loss of granuloma integrity, exacerbated necrosis, and higher bacterial load in survivors, although the precise cause of death was not directly established. These outcomes occurred despite the absence of classical clinical signs of sepsis and elevations in hallmark proinflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). PD-L1 blockade triggered a paradoxical cytokine profile (elevated IL-12p70 and IL-10) but failed to reprogram the neutrophil-dominated microenvironment.

Conclusion: These findings provide evidence that PD-1/PD-L1 signaling is associated with the maintenance of immune equilibrium and bacterial containment in chronic N. brasiliensis infection in our murine model. Although the absence of an isotype control remains a methodological limitation, anti-PD-L1 therapy was accompanied by severe immunopathology and reduced survival, highlighting potential risks of checkpoint inhibitors during underlying chronic infections.