Anti-leishmaniasis effect of Staphylococcus aureus Protein A on the size of the lesion and parasitic load

Tavalaei, Zahra; Zeinalian, Mehrdad; Khanahmad, Hossein; Hejazi, Hossein

Anti-leishmaniasis effect of Staphylococcus aureus Protein A on the size of the lesion and parasitic load

Authors

Department of Genetic and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

Abstract

Background: Many studies in the past have evaluated the role of immune system boosters in the treatment of leishmania major infection. Protein A (PA) is one of the structural components in peptidoglycan cell wall of gram-negative bacteria such as staphylococcus aurous which functions as a stimulator in the cellular immune system. The present study aims to evaluate the anti-inflammatory effect of PA on the recovery of leishmania major infection.
Materials and Methods: This study was conducted on 24 female Balb/c-infected mice. The experimental group received PA at a dose of 60 mg/kg for four weeks. There was no intervention for the negative control group; the third group received the solvent of PA and sterile H2O; and the positive control group received Amphotericin B at a dose of 1 mg/kg body weight. At the end of the treatment period, a real-time polymerase chain reaction (PCR) assay was performed to determine parasitic burden, and the size of the lesions was measured by caliper with an accuracy of 0.01 mm.
Results: Results showed that PA did slightly decrease the wound spread and growth but not to an extent that can be considered statistically significant. Also, differences in cycle threshold (Ct) values between the treated group and the untreated group was not impressive.
Conclusions: Although findings showed that PA isn't such a good candidate for leishmania treatment, it may still be suitable for therapies that use multiple drugs in combination to speed up the healing of leishmaniosis, an issue that merits evaluation in future studies.

Keywords

References

1.	Global leishmaniasis surveillance: 2019–2020, a baseline for the 2030 roadmap. Available from: https://www.who.int/publications-detail-redirect/who-wer9635-401-419. [Last accessed on 2022 Jan 31].
2.	Inceboz T. Epidemiology and Ecology of Leishmaniasis. Current Topics in Neglected Tropical Diseases. IntechOpen; 2019. Available from: https://www.intechopen.com/chapters/67175. [Last accessed on 2022 Jan 31].
3.	Gholami E, Oliveira F, Taheri T, Seyed N, Gharibzadeh S, Gholami N, et al. DNA plasmid coding for Phlebotomus sergenti salivary protein PsSP9, a member of the SP15 family of proteins, protects against Leishmania tropica. PLoS Negl Trop Dis 2019;13:e0007067.
4.	Aribi M. Macrophage bactericidal assays. Methods Mol Biol 2018;1784:135-49.
5.	Thomas DC. The phagocyte respiratory burst: Historical perspectives and recent advances. Immunol Lett 2017;192:88-96.
6.	Votintseva AA, Fung R, Miller RR, Knox K, Godwin H, Wyllie DH, et al. Prevalence of Staphylococcus aureus protein A (spa) mutants in the community and hospitals in Oxfordshire. BMC Microbiol 2014;14:63.
7.	Rigi G, Ghaedmohammadi S, Ahmadian G. A comprehensive review on staphylococcal protein A (SpA): Its production and applications. Biotechnol Appl Biochem 2019;66:454-64.
8.	Mazigi O, Schofield P, Langley DB, Christ D. Protein A superantigen: Structure, engineering and molecular basis of antibody recognition. Vol. 32, Protein Engineering, Design and Selection. Oxford University Press; 2019. p. 359-66.
9.	Zecconi A, Scali F. Staphylococcus aureus virulence factors in evasion from innate immune defenses in human and animal diseases. Immunol Lett 2013;150:12-22.
10.	Cellular and Molecular Immunology-9^th Edition. Available from: https://www.elsevier.com/books/cellular-and-molecular-immunology/abbas/978-0-323-47978-3. [Last accessed on 2021 Sep 21].
11.	Pidwill GR, Gibson JF, Cole J, Renshaw SA, Foster SJ. The Role of Macrophages in Staphylococcus aureus Infection. Front Immunol 2021;11:620339.
12.	Bröker BM, Mrochen D, Péton V. The T cell response to staphylococcus aureus. Pathogens 2016;5:31.
13.	Gómez MI, Lee A, Reddy B, Muir A, Soong G, Pitt A, et al. Staphylococcus aureus protein A induces airway epithelial inflammatory responses by activating TNFR1. Nat Med 2004;10:842-8.
14.	Xiao K, Liu C, Tu Z, Xu Q, Chen S, Zhang Y, et al. Activation of the NF-κ B and MAPK signaling pathways contributes to the inflammatory responses, but not cell injury, in IPEC-1 cells challenged with hydrogen peroxide. Oxid Med Cell Longev 2020;2020:5803639.
15.	Dri P, Gasparini C, Menegazzi R, Cramer R, Albéri L, Presani G, et al. TNF-induced shedding of TNF receptors in human polymorphonuclear leukocytes: Role of the 55-kDa TNF receptor and involvement of a membrane-bound and non-matrix metalloproteinase. J Immunol 2000;165:2165-72.
16.	Mishra A, Dwivedi PD, Verma AS, Ray PK. Mechanism of enhanced phagocytic response in protein a treated rat macrophages. Immunol Lett 1992;34:289-95.
17.	Krakauer T, Pradhan K, Stiles BG. Staphylococcal superantigens spark host-mediated danger signals. Front Immunol 2016;7:23.
18.	Leishmaniasis Clinical Presentation: History, Physical Examination. Available from: https://emedicine.medscape.com/article/220298-clinical. [Last accessed on 2020 Dec 04].
19.	Ghose AC, Mookerjee A, Sengupta K, Ghosh AK, Dasgupta S, Ray PK. Therapeutic and prophylactic uses of Protein A in the control of Leishmania donovani infection in experimental animals. Immunol Lett 1999;65:175-81.
20.	Carneiro PP, Conceição J, Macedo M, Magalhães V, Carvalho EM, Bacellar O. The role of nitric oxide and reactive oxygen species in the killing of leishmania braziliensis by monocytes from patients with cutaneous leishmaniasis. PLoS One 2016;11:e0148084.
21.	Horta MF, Mendes BP, Roma EH, Noronha FSM, Macêdo JP, Oliveira LS, et al. Reactive oxygen species and nitric oxide in cutaneous leishmaniasis. J Parasitol Res 2012;2012:203818.
22.	Roma EH, Macedo JP, Goes GR, Gonçalves JL, Castro W de, Cisalpino D, et al. Impact of reactive oxygen species (ROS) on the control of parasite loads and inflammation in Leishmania amazonensis infection. Parasit Vectors 2016;9:193.
23.	Panday A, Sahoo MK, Osorio D, Batra S. NADPH oxidases: An overview from structure to innate immunity-associated pathologies. Cell Mol Immunol 2015;12:5-23.
24.	Muñoz-Carrillo JL, Contreras-Cordero JF, Gutiérrez-Coronado O, Villalobos-Gutiérrez PT, Ramos-Gracia LG, Hernández-Reyes VE. Cytokine Profiling Plays a Crucial Role in Activating Immune System to Clear Infectious Pathogens. Immune Response Activation and Immunomodulation. IntechOpen; 2018.
25.	Zhou X, Yang W, Li J. Ca2+- and protein kinase C-dependent signaling pathway for nuclear factor-kappa B activation, inducible nitric-oxide synthase expression, and tumor necrosis factor-alpha production in lipopolysaccharide-stimulated rat peritoneal macrophages. J Biol Chem 2006;281:31337-47.
26.	Cosentino-Gomes D, Rocco-Machado N, Meyer-Fernandes JR. Cell signaling through protein kinase C oxidation and activation. Int J Mol Sci 2012;13:10697-721.
27.	Yahfoufi N, Alsadi N, Jambi M, Matar C. The Immunomodulatory and anti-inflammatory role of polyphenols. Nutrients 2018;10:E1618.
28.	Morris KR, Lutz RD, Choi HS, Kamitani T, Chmura K, Chan ED. Role of the NF-kappaB signaling pathway and kappa B cis-regulatory elements on the IRF-1 and iNOS promoter regions in mycobacterial lipoarabinomannan induction of nitric oxide. Infect Immun 2003;71:1442-52.
29.	Sinha P, Ray PK. Functional dichotomy of a 20-mer and 16-mer peptide derived from Staphylococcus aureus protein A: Importance of amino acid sequence. Immunopharmacol Immunotoxicol 2002;24:199-210.
30.	Agarwal DK, Ray PK. In vitro anti-oxidant property of protein-A of Staphylococcus aureus. Indian J Exp Biol 1991;29:1130-3.
31.	Catalona WJ, Ratliff TL, McCool RE. γ Interferon induced by S. aureus protein A augments natural killing and ADCC. Nature 1981;291:77-9.
32.	Kobayashi SD, DeLeo FR. Staphylococcus aureus protein A promotes immune suppression. mBio 2013;4:e00764-13.
33.	Thammavongsa V, Kim HK, Missiakas D, Schneewind O. Staphylococcal manipulation of host immune responses. Nat Rev Microbiol 2015;13:529-43.
34.	von Stebut E, Tenzer S. Cutaneous leishmaniasis: Distinct functions of dendritic cells and macrophages in the interaction of the host immune system with Leishmania major. Int J Med Microbiol 2018;308:206-14.
35.	Staphylococcal protein A inhibits complement activation by interfering with IgG hexamer formation \| PNAS. Available from: https://www.pnas.org/content/118/7/e2016772118. [Last accessed on 2021 Sep 21].
36.	Oliveira F, Bafica A, Rosato AB, Favali CBF, Costa JM, Cafe V, et al. Lesion size correlates with Leishmania antigen-stimulated TNF-levels in human cutaneous leishmaniasis. Am J Trop Med Hyg 2011;85:70-3.
37.	Elmahallawy EK, Alkhaldi AAM, Saleh AA. Host immune response against leishmaniasis and parasite persistence strategies: A review and assessment of recent research. Biomed Pharmacother 2021;139:111671.
38.	Host immune response against leishmaniasis and parasite persistence strategies: A review and assessment of recent research-ScienceDirect. Available from: https://www.sciencedirect.com/science/article/pii/S0753332221004534. [Last accessed on 2021 Sep 21].
39.	Khadem F, Uzonna JE. Immunity to visceral leishmaniasis: Implications for immunotherapy. Future Microbiol 2014;9:901-15.
40.	Smelt SC, Cotterell SE, Engwerda CR, Kaye PM. B cell-deficient mice are highly resistant to Leishmania donovani infection, but develop neutrophil-mediated tissue pathology. Jornal of Immunology 2000;164:3681-8.
41.	Fox PG, Schiavetti F, Rappuoli R, McLoughlin RM, Bagnoli F. Staphylococcal protein a induces leukocyte necrosis by complexing with human immunoglobulins. mBio 2021;12:e0089921.
42.	Blackwell JM, Fakiola M, Singh OP. Genetics, transcriptomics and meta-taxonomics in visceral leishmaniasis. Front Cell Infect Microbiol 2020;10:590888.

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