Helminth-induced arginase-1 exacerbates lung inflammation and disease severity in tuberculosis
Leticia Monin, … , Edward J. Pearce, Shabaana A. Khader
Leticia Monin, … , Edward J. Pearce, Shabaana A. Khader
Published November 16, 2015
Citation Information: J Clin Invest. 2015;125(12):4699-4713. https://doi.org/10.1172/JCI77378.
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Research Article Immunology

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

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.

Authors

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

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Figure 7

Arginase-1 expression during Mtb infection in genetically diverse mice and in humans correlates with increased inflammation and lung damage.

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Arginase-1 expression during Mtb infection in genetically diverse mice a...
Individual DO (n = 40) mice were aerosol infected with Mtb, and lung bacterial burden on d50 after infection was determined. Total area occupied by inflammatory lesions per lobe was quantified in H&E-stained formalin-fixed, paraffin embedded (FFPE) lung sections. RNAseq was performed on lung RNA from individual DO mice with the most SI and individual DO mice with EC, which also correlated with improved formation of lymphoid follicles within the granulomas. (A) Heat-map representation of significant genes. (B) The levels of Arg1 mRNA expression relative to Gapdh in lungs of individual DO mice with SI or EC was determined by RT-PCR. (C) Arginase-1 activity was determined in lung homogenates of individual DO, and linear correlation between arginase-1 activity and lung inflammatory area was determined (Pearson’s correlation, log2 scale). (D) Linear correlation analysis of arginase-1 activity in serum of patients with ATB and their lung damage score was carried out (Pearson’s correlation, n = 13). (E) The levels of ARG1 mRNA expression relative to GAPDH in blood monocyte cDNA derived from LTB (n = 5) and ATB (n = 6) human donors were determined. (F) Arginase-1 activity in serum from ATB patients with helminth coinfection and those without helminth coinfections was measured (n = 22 each). *P ≤ 0.05; unpaired, 2-tailed Student’s t test (B, E, and F) was used.