Research paper
The immunobiology of avian systemic salmonellosis

https://doi.org/10.1016/j.vetimm.2008.10.295Get rights and content

Summary

Avian systemic salmonellosis is primarily caused by Salmonella enterica serovar Gallinarum and serovar Pullorum causing the diseases Fowl Typhoid and Pullorum Disease respectively. During infection interaction with the immune system occurs in three main phases. First is invasion via the gastrointestinal tract. Infection with S. Pullorum or S. Gallinarum does not cause substantial inflammation, unlike S. Typhimurium or S. Enteritidis. Through in vitro models it was found that S. Gallinarum does not induce expression of CXC chemokines or pro-inflammatory cytokines such as IL-1β or IL-6, whilst in an in vivo model S. Pullorum infection leads to down-regulation of CXCLi1 and CXCLi2 in the ileum. The absence of flagella in S. Gallinarum and S. Pullorum means they are not recognised by TLR5, which is believed to play a key role in the initiation of inflammatory responses, though other pathogen-factors are likely to be involved. The second phase is establishing systemic infection. Salmonella invade macrophages and probably dendritic cells and are translocated to the spleen and liver, where replication occurs. Salmonella survival is dependent on the Salmonella pathogenicity island 2 type III secretion system, which inhibits antimicrobial activity by preventing fusion of lysosymes with the phagocytic vacuole and by modulation of MHC and cytokine expression. Studies in resistant and susceptible chicken lines have shown that the interaction with macrophages is central to the progression of infection or immunological clearance. Primary macrophages from resistant animals are more efficient in killing Salmonella through respiratory burst and by induction of cytokine expression including the initiation of protective Th1 responses that leads to the third phase. Where replication of Salmonella is not controlled the death of the animal usually results. If the innate immune system is not able to control replication then cellular and humoral responses, primarily mediated through Th1-associated cytokines, are able to clear infection. In S. Pullorum a significant number of animals develop persistent infection of splenic macrophages. Here we show preliminary evidence of modulation of adaptive immunity away from a Th1 response to facilitate the development of the carrier state. In carrier animals persistence may lead to reproductive tract and egg infection associated with a decline in CD4+ T cell numbers and function associated with the onset of sexual maturity in hens.

Introduction

In recent years we have begun to elucidate the role of the chicken immune system in the pathogenesis and protection to infection with Salmonella enterica. The course of S. enterica infection varies considerably depending on the infecting serovar and the genetic background of the host. Much work has focussed on understanding the mechanisms of enteric infection by S. enterica Typhimurium and enteric or egg infection by S. enterica serovar Enteritidis. These, along with many less invasive serovars, are a major public health issue as the result of human salmonellosis through the consumption of infected meat and eggs. Both S. Enteritidis and S. Typhimurium are capable of infecting a range of hosts. In the chicken infection of the gastrointestinal tract, particularly the caeca, may persist for several months. Systemic infection with these serovars is more transient and with the exception of newly hatched chicks cause little clinical disease (Barrow, 2000). In contrast S. enterica serovar Gallinarum and serovar Pullorum cause systemic disease only in a small range of avian species (Shivaprasad, 2000). S. Gallinarum causes Fowl Typhoid, a severe systemic infection affecting galliform birds of all ages typified by hepatospelnomegaly, anaemia and in the latter stages haemorrhage of the intestinal tract. Experimental infection with S. Gallinarum results in a mortality rate of 60% in 3 week old outbred chickens (Jones et al., 2001). Fowl Typhoid has been largely controlled in North America and Western Europe, though there is anecdotal evidence of a re-emergence in free range and organic production along with occasional outbreaks in commercial production (Cobb et al., 2005, Parmar and Davies, 2007). In contrast S. Gallinarum remains a major pathogen in many developing poultry industries including Asia and South America (Shivaprasad, 2000).

Pullorum Disease causes substantial mortality in chicks, but less frequently in birds of more than a week old (Wigley et al., 2001). S. Pullorum does however frequently develop a persistent carrier state. This can lead to reproductive tract infection in hens leading to ovarian abnormality, but more frequently to the transmission of infection to eggs and progeny without disease. S. Pullorum infection of poultry is prevalent in geographical locations similar to S. Gallinarum infection (Shivaprasad, 2000).

In this paper we review our current understanding of the interactions between the immune system and pathogen in systemic avian salmonellosis including some new data on the immunobiology of S. Pullorum infection.

Section snippets

Infection biology of avian salmonellosis

Avian systemic salmonellosis has three distinct phases during each of which there is significant interaction with the immune system (Table 1). The first is invasion via the gastrointestinal tract. The second phase is the establishment of systemic infection mainly as an intracellular infection of macrophages. Finally infection may be cleared by the immune response, the bird may succumb to the infection or a subclinical carrier state may develop.

Phase 1—intestinal invasion

The majority of avian Salmonella infections are as in mammals via the faecal oral route. In mammals Salmonella invades via the Peyer's patches and M cells in the ileum. Gastrointestinal infection induces enteritis in many species through a combination of the actions of secreted effectors of the Salmonella pathogenicity island 1 (SPI-1) type III secretion system and recognition of flagella and LPS via Toll-like receptors and other pattern recognition receptors (Gewirtz et al., 2000, Gewirtz et

Phase 2—development of systemic infection

Following invasion Salmonella are believed to be taken up by macrophages or dendritic cells and transported via the lymphatic system to the spleen and liver, though there is no firm experimental evidence of this (Mastroeni and Menager, 2003). The interaction between Salmonella and macrophage is the key to the progression of systemic infection in both mammals and birds (Barrow et al., 1994). Salmonella has developed systems to mediate its survival within macrophages, particularly the Salmonella

Phase 3—clearance, persistence or death

Following the establishment of systemic infection the chicken may clear or control the replication of bacteria as is the case in resistant inbred chickens, then clear infection through adaptive immunity. If replication is not controlled by innate immunity Salmonella replicates in the spleen and liver leading to pronounced hepatosplenomegaly, forming lesions in these organs. As infection, particularly with S. Gallinarum, progresses anaemia and septicaemia occur with Salmonella shed back into the

Immune clearance

Most evidence of the mechanisms of immune-clearance of Salmonella comes from experimental infection by S. Typhimurium or S. Enteritidis. The systemic stages of S. Typhimurium infection initially induce expression of pro-inflammatory cytokine, notably high levels of IL1-β and result in a transient hepatosplenomegaly. Clearance is associated primarily with a Th-1 dominated responses and high levels of interferon-γ expression at around 14–28 days post infection (Babu et al., 2004, Babu et al., 2003

The immunological basis of the carrier state and egg infection

The persistence of S. Pullorum in the face of both cellular and humoral responses is an interesting biological question and has practical implications in transmission of Salmonella to eggs. S. Pullorum persists within macrophages in the spleen and liver following experimental infection of 1 week old laying hens for at least 50 weeks post infection (Wigley et al., 2001). A strong antigen-specific antibody response and indeed cellular response may be determined following infection. After the

Conclusions

Avian systemic salmonellosis is of great interest both in terms of animal health and as a model for comparative biology. The use of S. Pullorum and S. Gallinarum infection models has been particularly useful in understanding the avian innate immune system in bacterial infections and increasingly in the actions of the adaptive immune system. Each of the three phases of systemic salmonellosis is of interest both immunologically and from the perspective of pathogen biology ranging from evasion of

Conflict of interest

None.

Acknowledgements

We wish to thank Adrian Smith and Richard Beal, Institute for Animal Compton and Jim Kaufmann, University of Cambridge, for their valuable contribution to discussions on the immunobiology of avian salmonellosis over the last decade. Paul Wigley wishes to thank the Biotechnology and Biological Sciences Research Council and DEFRA for financial support (BB/D007542/1).

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