Original Research ARTICLE
Human properdin modulates macrophage: Mycobacterium bovis BCG interaction via thrombospondin repeats (TSR) 4 and 5
- 1King Faisal Specialist Hospital & Research Centre, Saudi Arabia
- 2Biosciences, Brunel University London, United Kingdom
- 3University of Oxford, United Kingdom
Mycobacterium tuberculosis can proficiently enter phagocytes and diminish complement activation on its cell surface. Within phagocytes, the mycobacterium can suppress macrophage apoptosis and survive the intracellular environment. Complement regulatory proteins such as factor H may facilitate pathogen-macrophage interactions during tuberculosis infection. In this study, we show that M. bovis BCG binds properdin, an up-regulator of the complement alternative pathway. TSR4+5, a recombinant form of thrombospondin repeats 4 and 5 of human properdin expressed in tandem, which is an inhibitor of the alternative pathway, was also able to bind M. bovis BCG. Properdin and TSR4+5 were found to inhibit uptake of M. bovis BCG by THP-1 macrophage cells in a dose-dependent manner. Quantitative real-time PCR assays using transcripts from the THP-1 cells revealed elevated pro-inflammatory responses (TNF-α, IL-1β and IL-6) in the presence of properdin and TSR4+5, which gradually decreased over 6 hours. Correspondingly, anti-inflammatory responses (IL-10, TGF-β and IL-12) showed suppressed levels of expression in the presence of properdin, which gradually increased over 6 hours. Multiplex cytokine array analysis further revealed that properdin and TSR4+5 significantly enhanced the pro-inflammatory response (TNF-α, IL-1β and IL-1α) at 24 hours, which declined at 48 hours, whereas the anti-inflammatory response (IL-10 and IL-12) was suppressed. Our results suggest that properdin may interfere with mycobacterial entry into macrophages involving TSR4 and TSR5, particularly during the initial stages of infection, thus affecting the extracellular survival of the pathogen. This study offers novel insights into non-complement related functions of properdin, which may be independent of other complement proteins during host-pathogen interactions in tuberculosis. Thus, human properdin modulates macrophage-M. bovis BCG interaction via TSR4+5. Properdin residing in the granules of neutrophils is secreted upon stimulation and may also be produced by other cell types such as monocytes, bone marrow progenitor cell lines and T cells. The local production of properdin may be crucial for recruitment at sites of infection and in the control of M. tuberculosis infection.
Keywords: complement, Properdin, macrophage, Mycobacterium tuberculosis, M. bovis BCG, Phagocytosis, thrombospondin repeats
Received: 03 Jul 2017;
Accepted: 01 Mar 2018.
Edited by:Cees Van Kooten, Leiden University, Netherlands
Reviewed by:Michael Kirschfink, Universität Heidelberg, Germany
Lubka T. Roumenina, INSERM UMRS 1138, Cordeliers Research Center, Complement and diseases team
Copyright: © 2018 Al-Mozaini, Tsolaki, Abdul Aziz, Abozaid, Al-Ahdal, Kaur, Sim, Kishore and Kouser. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Dr. Uday Kishore, PHD., Brunel University London, Biosciences, School of Health Sciences and Social Care, Heinz Wolff Building, Brunel University, Uxbridge, UB8 3PH, United Kingdom, firstname.lastname@example.org