How Mannheimia haemolytica defeats host defence through a kiss of death mechanism Laurent Zecchinon, Thomas Fett, Daniel Desmecht To cite this version: Laurent Zecchinon, Thomas Fett, Daniel Desmecht. How Mannheimia haemolytica defeats host de- fence through a kiss of death mechanism. Veterinary Research, BioMed Central, 2005, 36 (2), pp.133- 156. 10.1051/vetres:2004065. hal-00902968 HAL Id: hal-00902968 https://hal.archives-ouvertes.fr/hal-00902968 Submitted on 1 Jan 2005 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Vet. Res. 36 (2005) 133–156 133 © INRA, EDP Sciences, 2005 DOI: 10.1051/vetres:2004065 Review article How Mannheimia haemolytica defeats host defence through a kiss of death mechanism Laurent ZECCHINON, Thomas FETT, Daniel DESMECHT* Department of Pathology, Faculty of Veterinary Medicine, University of Liège, FMV Sart-Tilman B43, 4000 Liège, Belgium (Received 22 June 2004; accepted 6 October 2004) Abstract – Mannheimia haemolytica induced pneumonias are only observed in goats, sheep and cattle. The bacterium produces several virulence factors,whose principal ones are lipopolysaccharide and leukotoxin. The latter is cytotoxic only for ruminant leukocytes, a phenomenon that is correlated with its ability to bind and interact with the ruminant β2-integrin Lymphocyte Function-associated Antigen 1. This paper globally reviews all the information available on host-pathogen interactions underlying respiratory mannheimiosis (formerly pasteurellosis), from the stable and the Petri dish to the biochemical cascade of events triggered by the leukotoxin inside ruminant leukocytes. One conclusion can be made: the most widespread cattle respiratory disease with the most important impact on beef production worldwide, is probably due to a tiny ruminant-specific focal variation in the CD18- and/or CD11a-expressing genes. Mannheimia haemolytica / leukotoxin / β2–integrin / ruminant Table of contents 1. Introduction...................................................................................................................................... 134 2. Bovine pneumonias.......................................................................................................................... 134 3. Mannheimia haemolytica................................................................................................................. 134 3.1. Diversity.................................................................................................................................. 134 3.2. Antibiotic resistance................................................................................................................ 135 3.3. Pathogenesis............................................................................................................................ 135 3.4. Clinical signs and lesions ........................................................................................................ 136 3.5. Known host-pathogen interactions.......................................................................................... 136 4. Leukotoxin ....................................................................................................................................... 137 4.1. The main virulence weapon .................................................................................................... 137 4.2. Production and activation........................................................................................................ 137 4.3. Gene organisation and transcriptional regulation ................................................................... 137 4.4. Natural diversity...................................................................................................................... 138 5. The leukotoxin targets(s) ................................................................................................................. 138 5.1 Macrophages and neutrophils ................................................................................................. 138 5.2. β2-integrins ............................................................................................................................. 139 5.3. Lymphocyte Function–associated Antigen 1 .......................................................................... 139 * Corresponding author: [email protected] 134 L. Zecchinon et al. 6. The lipopolysaccharide.....................................................................................................................140 7. Modes of action ................................................................................................................................141 7.1. Apoptosis/necrosis ...................................................................................................................141 7.2. Death pathways........................................................................................................................141 7.3. Pore formation .........................................................................................................................146 7.4. Molecular synergies with other pathogens ..............................................................................147 8. Conclusion and perspective..............................................................................................................147 1. INTRODUCTION On the morbidity level, pneumonias do exert, by far, the most severe impact: they Man understood many centuries ago that are responsible for about 75% of clinically it would be more valuable to breed rather visible diseases [52, 85] with average res- than to hunt animals like cattle, sheep and piratory morbidity rates ranging from 15 to goats but he quickly realised the difficulty 45% [95]. in warranting good animal health. Several On the mortality level, pneumonias are practices such as sanitary slaughtering, quar- directly incriminated in about 45 to 55% of antining animals, importing restrictions, vac- the cases [52, 174]. cination and medical treatments have been On the production costs level, medical intended to control, if not eradicate, ill- treatments generate about eight percent of nesses. In the same way, antibiotics are used total production costs, without making an to fight against pathogens that have found allowance for losses due to lower zootech- in highly concentrated breeding conditions nical performances [65, 66]. a choice niche extremely favourable for the The main biological causes of bovine contagion. Nevertheless, it is now clearly pneumonias are (i) the lungworm dictyo- established that prophylaxy and metaphy- caulus viviparus, (ii) the viruses – the Her- laxy create a selective pressure towards the pes Virus-1, the Respiratory Syncytial Virus, emergence of resistant strains which in turn the Parainfluenza-3 virus, the Viral Diarrhea- could lead to new pathologies [55]. Mucosal Disease, the adenovirus, the coro- navirus and (iii) the bacteria – Mannheimia haemolytica, Pasteurella multocida, Myco- plasma bovis and Arcanobacterium pyo- 2. BOVINE PNEUMONIAS genes [51, 86, 87, 111, 131, 189]. Most authors consider that, whatever the The decrease of animal diseases (and causative factor (environment, virus, para- bovine diseases in particular) has thus become site), the bacterium M. haemolytica is sys- an absolute priority since it is well-known tematically found as a complicating agent. that medical cost has the main impact on Consequently, we will further focus on this farm profitability, independently of market bacterium and the way it acts. prices [60]. These costs are unequivocally brought by respiratory diseases [65, 119, 157] since about 25% of the calves experi- 3. MANNHEIMIA HAEMOLYTICA ence at least one episode of respiratory dis- ease during the first year of life, with fre- 3.1. Diversity quencies over six birth years ranging from 14 to 38%. The incidence of bovine respi- Mannheimia haemolytica is a weakly ratory diseases is greater in male calves than hemolytic, gram-negative coccobacillus with in female calves during both preweaning the following complete taxonomy: superking- and feedlot periods [133]. dom Bacteria; phylum Proteobacteria; class Mannheimiosis (pasteurellosis) 135 Gammaproteobacteria; order Pasteurella- of their capsules, serotypes A1 and A6 are les; family Pasteurellaceae; genus Mann- extremely similar [39, 130]. heimia [166]. The bacterium has been the subject of 3.2. Antibiotic resistance extensive reclassification in the past: first called Bacterium bipolare multocidum by Due to the often ineffective immunopro- Theodore Kitt in 1885 [96], it was renamed phylactic measures taken, antimicrobials Pasteurella haemolytica in 1932 [135] and are used to a large extent for prophylaxy, classified into two biotypes, A and T, based metaphylaxy or growth-stimulation. More- on its ability to ferment arabinose and tre- over, the delay of analysing isolates from ill halose, respectively [154]. There were 13 A animals in a diagnostic lab makes it difficult serotypes and four