Document Type

Article

Publication Date

12-15-2021

Publication Title

The Journal of infectious diseases

Keywords

JGM, Animals, Immunity, Macrophage Activation, Macrophages, Mice, Mycobacterium tuberculosis, T-Lymphocytes, Tuberculosis

JAX Source

J Infect Dis . 2021 Dec 15;224(12):2170-2180.

Volume

224

Issue

12

First Page

2170

Last Page

2180

ISSN

1537-6613

PMID

34739044

DOI

10.1093/infdis/jiab558

Grant

This work was supported by the South African Medical Research Council (SAMRC) and its Division of Research Capacity Development under the SAMRC Internship Scholarship Programme (from funding received from the South African National Treasury to L. H.; SAMRC Intercalated Bursary to S.R.N.S.); the International Centre for Genetic Engineering & Biotechnology (Arturo Falaschi fellowships from the Cape Town Component to M. O. and J. E. C. and support to F. B.); the Ministry of Education, Culture, Sports, Science and Technology of the Japanese government (research grant for the Special Coordination Funds for Promoting Science and Technology to H. S.); the National Research Foundation (NRF)/Department of Science and Technology (DST)–South African Research Chair Initiative, NRF Competitive Programme for Unrated Researchers; the DST/NRF Collaborative Postgraduate Training Programme; the Brazil, Russia, India, China and South Africa (BRICS) Multilateral Joint Science and Technology Research Collaboration (grant 110482 to R. G.); and the Wellcome Centre for Infectious Diseases Research in Africa (203135Z/16/Z fund supporting biosafety level 3 facilities and equipment).

Abstract

BACKGROUND: Interleukin 4 (IL-4i1)-induced gene 1 encodes L-phenylalanine oxidase that catabolizes phenylalanine into phenylpyruvate. IL-4i1 is mainly expressed by antigen-presenting cells (APCs), inhibits T-cell proliferation, regulates B-cell activation, modulates T cell responses, and drives macrophage polarization, but its role in bacterial infections is understudied.

METHODS: We evaluated IL-4i1 deletion in macrophages and mice on infection with virulent H37Rv and W-Beijing lineage hypervirulent HN878 Mycobacterium tuberculosis (Mtb) strains. The bacterial growth and proinflammatory responses were measured in vitro and in vivo. Histopathological analysis, lung immune cell recruitment, and macrophage activation were assessed at the early and chronic stages of Mtb infection.

RESULTS: IL-4i1-deficient (IL-4i1-/-) mice displayed increased protection against acute H37Rv, HN878 and chronic HN878 Mt infections, with reduced lung bacterial burdens and altered APC responses compared with wild-type mice. Moreover, "M1-like" interstitial macrophage numbers, and nitrite and Interferon-γ production were significantly increased in IL-4i1-/- mice compared with wild-type mice during acute Mtb HN878 infection.

CONCLUSIONS: Together, these data suggest that IL-4i1 regulates APC-mediated inflammatory responses during acute and chronic Mtb infection. Hence, IL-4i1 targeting has potential as an immunomodulatory target for host-directed therapy.

Comments

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

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