Pasteurella pneumotropica Evades the Human Complement System by Acquisition of the Complement Regulators Factor H and C4BP

Pasteurella pneumotropica Evades the Human Complement System by Acquisition of the Complement Regulators
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Pasteurella pneumotropica Evades the Human Complement System by Acquisition of the Complement Regulators Factor H and C4BP Alfredo Sahagu´n-Ruiz1, Adriana Patricia Granados Martinez2, Leandro Carvalho Dantas Breda2, Tatiana Rodrigues Fraga2, Mo´nica Marcela Castiblanco Valencia2, Angela Silva Barbosa3, Lourdes Isaac2* 1 Departamento de Microbiologı´a e Inmunologı´a, Facultad de Medicina Veterinaria y Zootecnia, Universidad Nacional Auto´noma de Me´xico, Mexico City, Mexico, 2 Departamento de Imunologia, Instituto de Cieˆncias Biome´dicas, Universidade de Sa˜o Paulo, Sa˜o Paulo, Brazil, 3 Laborato´rio de Bacteriologia, Instituto Butantan, Sa˜o Paulo, Brazil

Abstract Pasteurella pneumotropica is an opportunist Gram negative bacterium responsible for rodent pasteurellosis that affects upper respiratory, reproductive and digestive tracts of mammals. In animal care facilities the presence of P. pneumotropica causes severe to lethal infection in immunodeficient mice, being also a potential source for human contamination. Indeed, occupational exposure is one of the main causes of human infection by P. pneumotropica. The clinical presentation of the disease includes subcutaneous abscesses, respiratory tract colonization and systemic infections. Given the ability of P. pneumotropica to fully disseminate in the organism, it is quite relevant to study the role of the complement system to control the infection as well as the possible evasion mechanisms involved in bacterial survival. Here, we show for the first time that P. pneumotropica is able to survive the bactericidal activity of the human complement system. We observed that host regulatory complement C4BP and Factor H bind to the surface of P. pneumotropica, controlling the activation pathways regulating the formation and maintenance of C3-convertases. These results show that P. pneumotropica has evolved mechanisms to evade the human complement system that may increase the efficiency by which this pathogen is able to gain access to and colonize inner tissues where it may cause severe infections. Citation: Sahagu´n-Ruiz A, Granados Martinez AP, Breda LCD, Fraga TR, Castiblanco Valencia MM, et al. (2014) Pasteurella pneumotropica Evades the Human Complement System by Acquisition of the Complement Regulators Factor H and C4BP. PLoS ONE 9(10): e111194. doi:10.1371/journal.pone.0111194 Editor: Brian Stevenson, University of Kentucky College of Medicine, United States of America Received May 5, 2014; Accepted September 29, 2014; Published October 27, 2014 Copyright: ß 2014 Sahagu´n-Ruiz et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files. Funding: Funding provided by Grant #2010/50043-0, Fundac¸a˜o de Amparo a` Pesquisa do Estado de Sa˜o Paulo (FAPESP). A.S.R. was supported by a fellowship from the Programa de Apoyos para la Superacio´n del Personal Acade´mico (PASPA-DGAPA) from Universidad Nacional Auto´noma de Me´xico (UNAM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * Email: [email protected]

presentation of the disease includes cellulitis, subcutaneous abscesses, respiratory tract colonization and systemic alterations [5]. In addition, specific reports of humans infections by P. pneumotropica include a wide variety of clinical findings, such as: left-sided and right-sided endocarditis [6,7]; pneumonia in patients with a anti-trypsin deficiency [8] and HIV [9]; meningitis [10], osteomyelitis and arthritis associated with dog bites [11]; septicemia in an elderly woman living with cats [12]; peritonitis in a patient receiving dialysis [13]; and epidural abscess [14]. Given the ability of P. pneumotropica to fully disseminate in the organism, it is plausible that it may have evolved different mechanisms to escape from the attack of the immune system. The complement system plays an important role in innate and acquired immunity. This system can be activated by three independent pathways: the classical, the alternative and the lectin pathways. Once activated, several important biological functions contribute towards pathogen elimination, including: a) production of opsonins (fragments iC3b, C3b, C3d and C4d) that enhance phagocytosis; b) release of chemotactic factors (fragments C3a and C5a) that attract inflammatory cells to the activation site; c)

Introduction The genus Pasteurella comprises a group of Gram negative bacteria that are commensal and opportunistic pathogens. They affect mainly the respiratory and genital tracts but can also cause systemic infections, responsible for relevant diseases in domestic and wild animals, including, fowl cholera, hemorrhagic septicemia and pneumonia in cattle, swine atrophic or purulent rhinitis in rabbits [1]. Pasteurella multocida was one of the first pathogenic bacteria studied and the first live vaccine ever produced from attenuated bacteria [2]. P. multocida may be present in the normal bacterial flora residing within the intestinal, respiratory and genital mucosa of various animals. Another species of the same genus, P. pneumotropica, is widely encountered as part of the normal flora of the upper respiratory tract of laboratory animals where it is considered an opportunistic pathogen capable of causing pulmonary lesions [3]. It may also cause abortion, and it has been isolated from the lung and spleen of infected mouse fetuses [4]. One of the main sources of human contamination by Pasteurella spp is occupational exposure, although infection may also be associated with pet bites and scratching. The clinical PLOS ONE | www.plosone.org

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October 2014 | Volume 9 | Issue 10 | e111194

P. pneumotropica Binds FH and C4BP

production of anaphylatoxins that trigger mast cell and basophil degranulation (fragments C3a, C4a and C5a) releasing inflammatory mediators; d) cell lysis caused by the membrane attack complex (C5b-9n); e) proliferation of B lymphocytes and increased antibody production (fragment C3d and complement receptor-2); and, f) generation of fragment C3d which acts as an adjuvant, reviewed [15]. To prevent activation on self-cells and excessive consumption of complement proteins, several regulatory molecules are present in a soluble form in the plasma or as part of the host cell membrane. Factor H (FH) regulates the alternative pathway (activated independently of antibodies) and C4b-binding protein (C4BP) regulates both the classical (antibody-dependent) and the lectin (innate immunity) pathways [16,17]. These regulatory proteins are present at relatively high concentrations in plasma (FH = 442.76105.8 mg/ml, and C4BP = 334.6682.6 mg/ml) [18]. FH and C4BP act as co-factors of the serine protease Factor I (FI) in the cleavage of C3b and C4b, respectively. They can also accelerate C3-convertase decay (C3bBb for the alternative pathway and C4b2a in the classical and lectin pathways) [15– 21]. In this way, FH and C4BP are soluble regulators that prevent a continued cascade activation of the three complement pathways. The acquisition of FH and C4BP by human pathogens constitutes an important evasion mechanism, since it blocks the complement activation on their surfaces [22–24]. Studies on the role of complement to eliminate bacteria of the genus Pasteurella performed to date have employed P. multocida. It has been demonstrated that complement resistant strains are more virulent than susceptible ones. Snipes and Hirsh [25] reported a higher susceptibility of an acapsular mutant (P1059-1 A) of P. multocida to lysis mediated by complement proteins present in turkey plasma when compared to that observed for the parental P1059-1 strain. Hansen and Hirsh [26] subsequently observed that resistance of P. multocida to turkey serum was associated with encapsulation, since non-encapsulated strains and bacteria cultured in media with hyaluronidase were susceptible to complement lysis. Consumption of complement was observed in serum after incubation with either encapsulated or non-encapsu-

lated bacteria. It was therefore suggested that in spite of activation of the complement system on the bacterial surface, the capsule somehow acts as a shield against the insertion of the membrane attack complex into the outer membrane [26], a mechanism that is distinct from one that would work via inhibition of complement activation. On the other hand, the contribution of the capsule in complement resistance is not completely clear: Boyce and Adler [27] constructed a P. multocida mutant impaired in capsule synthesis that was just as resistant to complement bovine serum proteins as the wild type strain. However, the acapsular P. multocida mutant was more susceptible to phagocytosis than the wild type. Blau et al [28] observed that clinical isolates of P. multocida or P. haemolytica (now Mannheimia haemolytica) varied considerably in their resistance or susceptibility to lysis by fresh bovine serum. Serum sensitivity of P. multocida was observed even in the presence of EGTA-MgCl2 (conditions in which the classical and lectin pathways are not activated) indicating that the alternative pathway was likely the most important pathway activated by this pathogen. Despite all these studies with P. multocida, to our knowledge, the role of the complement system in P. pneumotropica has not yet been investigated. This work aimed to analyze the survival of P. pneumotropica when incubated with non-immune human serum. Here we investigated a possible evasion mechanism employed by this bacterium to evade complement, by the ac...

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