Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 125, Issue 12, Pages 4699-4713Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI77378
Keywords
-
Categories
Funding
- Washington University in St. Louis, Children's Hospital of Pittsburgh
- NIH [HL105427, AI032573, AI108725]
- Children's Hospital of Pittsburgh Research Advisory Committee Grant from Children's Hospital of Pittsburgh of the UPMC Health System
- American Lung Association Senior Research Training Fellowship [RT-30592]
- Department of Medicine, University of Rochester [U19 AI91036]
Ask authors/readers for more resources
Parasitic helminth worms, such as Schistosoma mansoni, are endemic in regions with a high prevalence of tuberculosis (TB) among the population. Human studies suggest that helminth coinfections contribute to increased TB susceptibility and increased rates of TB reactivation. Prevailing models suggest that T helper type 2 (Th2) responses induced by helminth infection impair Th1 immune responses and thereby limit Mycobacterium tuberculosis (Mtb) control. Using a pulmonary mouse model of Mtb infection, we demonstrated that S. mansoni coinfection or immunization with S. mansoni egg antigens can reversibly impair Mtb-specific T cell responses without affecting macrophage-mediated Mtb control. Instead, S. mansoni infection resulted in accumulation of high arginase-1-expressing macrophages in the lung, which formed type 2 granulomas and exacerbated inflammation in Mtb-infected mice. Treatment of coinfected animals with an antihelminthic improved Mtb-specific Th1 responses and reduced disease severity. In a genetically diverse mouse population infected with Mtb, enhanced arginase-1 activity was associated with increased lung inflammation. Moreover, in patients with pulmonary TB, lung damage correlated with increased serum activity of arginase-1, which was elevated in TB patients coinfected with helminths. Together, our data indicate that helminth coinfection induces arginase-1-expressing type 2 granulomas, thereby increasing inflammation and TB disease severity. These results also provide insight into the mechanisms by which helminth coinfections drive increased susceptibility, disease progression, and severity in TB.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available