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

J Clin Invest. 2015 Dec;125(12):4699-713. doi: 10.1172/JCI77378. Epub 2015 Nov 16.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arginase / blood*
  • Female
  • Granuloma / enzymology
  • Granuloma / microbiology
  • Granuloma / parasitology
  • Granuloma / pathology
  • Humans
  • Lung / metabolism*
  • Lung / microbiology
  • Lung / parasitology
  • Lung / pathology
  • Macrophages / enzymology*
  • Macrophages / pathology
  • Male
  • Mice
  • Mice, Transgenic
  • Mycobacterium tuberculosis*
  • Schistosoma mansoni*
  • Schistosomiasis mansoni / blood*
  • Schistosomiasis mansoni / microbiology
  • Schistosomiasis mansoni / pathology
  • Tuberculosis, Pulmonary / blood*
  • Tuberculosis, Pulmonary / parasitology
  • Tuberculosis, Pulmonary / pathology

Substances

  • Arg1 protein, mouse
  • Arginase
  • arginase I, human