Helminth-induced arginase-1 exacerbates lung inflammation and disease severity in tuberculosis

Leticia Monin, Kristin L. Griffiths, Wing Y. Lam, Radha Gopal, Dongwan D. Kang, Mushtaq Ahmed, Anuradha Rajamanickam, Alfredo Cruz-Lagunas, Joaquín Zúñiga, Subash Babu, Jay K. Kolls, Makedonka Mitreva, Bruce A. Rosa, Rosalio Ramos-Payan, Thomas E. Morrison, Peter J. Murray, Javier Rangel-Moreno, Edward J. Pearce, Shabaana A. Khader

Research output: Contribution to journalArticlepeer-review

60 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)4699-4713
Number of pages15
JournalJournal of Clinical Investigation
Volume125
Issue number12
DOIs
StatePublished - Dec 2015

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