Preexisting helminth infection impairs immunity against subsequent M. tuberculosis infection, in part by inducing alternatively activated macrophages.

The lengthy course of treatment with currently used anti-mycobacterial drugs and the resulting emergence of drug-resistant strains have intensified the need for alternative therapies against Mycobacterium tuberculosis (Mtb), the etiologic agent of tuberculosis. We show that Mtb and Mycobacterium marinum use Abl and related tyrosine kinases for entry and intracellular survival in macrophages. In mice, the Abl-family tyrosine kinase inhibitor, imatinib (Gleevec®), when administered prophylactically or therapeutically, reduced both the number of granulomatous lesions and bacterial load in infected organs, and was also effective against a rifampicin-resistant strain. Further, when co-administered with current first-line drugs, rifampicin or rifabutin, imatinib acted synergistically. These data implicate host tyrosine kinases in entry and intracellular survival of mycobacteria, and suggest that imatinib may have therapeutic efficacy against Mtb. Because imatinib targets host, it is less likely to engender resistance compared to conventional antibiotics, and may decrease the development of resistance against co-administered drugs.

Nitric oxide (NO) defends against intracellular pathogens but its synthesis must be regulated due to cell and tissue toxicity. During infection, macrophages import extracellular arginine to synthesize NO, generating the byproduct citrulline. Accumulated intracellular citrulline is thought to fuel arginine synthesis catalyzed by argininosuccinate synthase (Ass1) and argininosuccinate lyase (Asl), which would lead to abundant NO production. Instead, we find that citrulline is exported from macrophages during early stages of NO production with < 2% retained for recycling via the Ass1-Asl pathway. Later, extracellular arginine is depleted, and Ass1 expression allows macrophages to synthesize arginine from imported citrulline to sustain NO output. Ass1-deficient macrophages fail to salvage citrulline in arginine-scarce conditions, leading to their inability to control mycobacteria infection. Thus, extracellular arginine fuels rapid NO production in activated macrophages, and citrulline recycling via Ass1 and Asl is a fail-safe system that sustains optimum NO production.

Whether helminthes affect tuberculosis (TB) disease is still an open question and clinical trials are warranted to determine at the population level whether helminthes enhance TB incidence and transmission and diminish the protective immune response to vaccines. Consequently, mass deworming of infected individuals could contribute toward overall improvement of global public health.