Campylobacter Infections in Ruminants

Campylobacter‐induced reproductive losses in ruminants, abortion and infertility, are common and incur a significant economic burden worldwide (Skirrow 1994; Michi et al. 2016; Sahin et al. 2017b). The primary Campylobacter spp. associated with these clinical conditions are C. fetus and C. jejuni (Figure 18.1). There are two C. fetus subspecies of importance to ruminant health: C. fetus subsp. venerealis (Cfv) and C. fetus subsp. fetus (Cff). While Cfv is restricted to bovine genital tract and causes venereally transmitted infectious infertility in cattle, Cff has a broader host range, is transmitted via the fecal–oral route, and is associated with abortions in sheep, cattle and goats. Besides Cff, C. jejuni is also a leading cause of sheep abortion storms and occasionally induces sporadic abortions in goats and cows.

Sheep

Campylobacter infection is a major cause of infectious abortion in sheep worldwide (Van Engelen et al. 2014; Sahin et al. 2017b). The disease is also known as epizootic or vibrionic abortion and is typically manifested as large outbreaks (epidemics) of fetal loss in the last trimester of pregnancy. Etiologically, multiple pathogens are implicated in sheep abortion, and the proportion attributed to Campylobacter varies considerably with regions and countries. However, Campylobacter usually ranks at the top, with a flock abortion rate of 5–50%. The Campylobacter species associated with ovine abortion are primarily C. jejuni and Cff (Skirrow 1994; Sahin et al. 2017b). Although they are pathogenic to pregnant ewes, both species, especially C. jejuni, commonly reside in the ruminant intestine and/or gall bladder as commensal organisms. Notably, they share many common ecological, epidemiological and pathological features in ruminants.

There appears a great geographic variation in the main Campylobacter spp. associated with ovine abortion. In general, and historically, Cff has been the main Campylobacter species associated with sheep abortions worldwide, even though the reported abortion cases induced by C. jejuni has been on the rise in recent years (Wu et al. 2014b; Sahin et al. 2017b). In major sheep producing countries, such as the United Kingdom and New Zealand, Cff continues to be the leading Campylobacter species causing abortion storms in flocks (Mannering 2003; Wu et al. 2014b). However, in North America, especially in the United States, there has been a remarkable species shift in the etiology of Campylobacter‐associated ovine abortion since the late 1980s. C. jejuni has displaced Cff as the predominant abortifacient species, accounting for more than 90% of abortions during the past two decades (Sahin et al. 2017b). In Denmark, where Cff was previously the only known Campylobacter species associated with ovine abortion, a recent study identified C. jejuni as the cause of abortion outbreaks in sheep flocks for the first time (Wolf‐Jackel et al. 2020). In other countries, very limited information is available on species distribution of Campylobacter‐associated sheep abortion.

Genetically, Cff and C. jejuni strains recovered from sheep abortions from different lambing seasons and farms tend to show high genetic diversity, while strains from a single abortion storm are usually homologous (Wu et al. 2014b; Sahin et al. 2017b). An exception has been reported in the United States, where a single genetic clone (ST‐8) of C. jejuni, named “clone SA” (for sheep abortion), has expanded to become the primary cause (responsible for > 90% cases) of Campylobacter‐induced abortion in sheep (Wu et al. 2014b; Sahin et al. 2017b). C. jejuni clone SA is resistant to tetracycline, the only drug currently approved for the control of Campylobacter abortions in sheep in the United States, and is highly abortifacient as demonstrated by challenge in different animal models (Burrough et al. 2009; Wu et al. 2016; Wu et al. 2020). It is also a zoonotic pathogen and has been implicated in foodborne disease outbreaks in humans due to consumption of raw milk (Sahin et al. 2012).

Sheep abortion induced by Cff and C. jejuni is transmitted by the fecal–oral route, not by the venereal mode or genital infection, ascending from the gastrointestinal tract (Skirrow 1994; Grogono‐Thomas et al. 2003; Sahin et al. 2017b). These two Campylobacter species, especially C. jejuni, are often carried in the intestinal tract and gallbladder of sheep and other ruminants, and thus are shed in feces. Despite the ubiquitous distribution of Campylobacter on sheep farms, only a fraction of exposures lead to clinical abortion. When it occurs, abortion typically starts with just one or two ewes first in a flock and then proceeds as a sharp rise (abortion storm) in the number affected animals within a couple of weeks. Although it is difficult to determine the initial infection source(s), it may include introduction of new sheep from flocks with a history of abortion, exposure directly to aborted materials (e.g. placenta) and vaginal discharge, and consumption of pasture, feed and water contaminated by the products of abortion (e.g. placenta and uterine discharge). Aborted placenta and uterine discharge of ewes contain large numbers of Campylobacter, which is thought to be a very significant source of infection for susceptible ewes in a flock (Sanad et al. 2014; Yaeger et al. 2021).

Campylobacter Infections in Poultry

Campylobacter spp. are generally commensals in poultry. For example, C. jejuni and C. coli commonly colonize the intestine of poultry (both chickens and turkeys) without inducing pathologic lesions or overt disease (Hermans et al. 2012; Sahin et al. 2015). One exception is C. hepaticus, which was recently determined to be the etiological agent of SLD in layer chickens (Figure 18.1; Van et al. 2016; Van et al. 2017a). SLD was first reported in the United States and Canada in the 1950s and 1960s, respectively (Courtice et al. 2018; Crawshaw 2019). However, the etiological agent was not identified until 2015 (Crawshaw et al. 2015). SLD is mostly seen in free‐ranging layers, and occurs less frequently in caged layers and other types of chickens (Courtice et al. 2018; Crawshaw 2019). Historically, SLD peaked in the early 1960s, but it nearly vanished from Europe and North America by the early 1980s. However, from the late 1980s, SLD re‐emerged in laying hens in Australia and UK and then worldwide (Courtice et al. 2018; Crawshaw 2019). The near disappearance and then re‐emergence of SLD coincided with changes in production practices, from free range to battery cages and then a shift to free range in response to the welfare concerns about cage operations (Department for Environment, Food and Rural Affairs 2022). Thus, the incidence of SLD appears to be correlated with the magnitude of the free‐range operations. The reason for this correlation is unknown, but it was speculated that multi‐tier housing and automated removal of feces in the caged layer industry might have prevented exposure of birds to external sources of infection and thereby diminished transmission of SLD (Duncan 2001).

Birds can be infected by C. hepaticus as young as 12 weeks of age and may carry the organism in the intestine for many weeks before onset of clinical SLD (Phung et al. 2019). Epidemiologically, the first occurrence of SLD in flocks is often at the peak of lay. It was speculated that metabolic changes associated with rapid increase in egg production could increase the susceptibility of layer birds to C. hepaticus and its virulence mechanisms (Courtice et al. 2018; Moore et al. 2019). The exact source of infection for a flock is unclear but is likely to be environmental. For example, a recent study detected C. hepaticus in various environmental samples such as feces, water, insects, and rodents on SLD‐positive farms as well as farms with no clinical SLD (Phung et al. 2019). The wide distribution of C. hepaticus in these samples could explain the higher incidence of SLD in free‐range operations, where layer chickens have more opportunities to interact with diverse environmental factors such as wild birds, flies, and rodents.

Campylobacter‐Induced Reproductive Loss in Ruminants

Spotty Liver Disease in Poultry

Clinically, SLD causes rapid decrease in egg production accompanied by increase in mortality, which may last for several weeks. Egg production drop and mortality vary with different outbreaks, of 10–35% and 0.5–15%, respectively (Grimes and Reece 2011). Moribund birds are not commonly detected as death generally occurs quickly (Grimes and Reece 2011; Crawshaw et al. 2015). Even when the outbreak is over, egg production can remain depressed compared with pre‐outbreak levels (Crawshaw and Young 2003). Epidemiologically, SLD outbreaks occur most frequently when layer birds reach the peak of lay (Crawshaw 2019), although variations in this association have been reported. For example, an Australian study of 17 SLD outbreaks revealed that the flock age for SLD outbreaks varied from 22 weeks to 80 weeks, with an average of 33.8 weeks (Crawshaw 2019). Previously, SLD was referred to as “summer hepatitis,” due to the higher incidence in summer months; however, recent observations indicate that the disease occurs all year round (Phung et al. 2019).

Pathologically, characteristic lesions of SLD are grayish, white or cream necrosis spots (1–2 mm in diameter) on the surface of liver (Figure 18.2). The necrosis foci are usually scattered throughout liver lobes but may be more densely visible at the edges of liver lobes (Crawshaw and Young 2003; Crawshaw 2019). The infected liver may be slightly enlarged and fibrinous (Crawshaw and Young 2003; Scott 2016). Pathological changes in other organs may also occur, such as enlarged and mottled spleen, mild enteritis, and excessive pericardial and peritoneal fluid (Crawshaw and Young 2003; Grimes and Reece 2011). Microscopically, liver lesions are typically represented by an acute, randomly distributed, focal, and necrotic hepatitis with fibrinous exudate (Figure 18.2; Scott 2016). In the spleen, fibrinoid necrosis and fibrin thrombi as well as reticular‐cell hyperplasia can be observed. In the small and large intestine, inflammation may occur with infiltration of lymphocytes, plasma cells, and focal heterophil in lamina propria (Scott 2016).

Sheep Abortion

C. jejuni and Cff are transmitted by the fecal–oral route and colonize in the intestinal tract and less frequently in the gallbladder without causing clinical disease in non‐pregnant animals (Acik and Cetinkaya 2006; Sahin et al. 2017b). In pregnant ewes, the organisms may spread systemically to induce clinical abortion (Figure 18.1). What triggers an otherwise commensal organism to become pathogenic and cause abortion are not fully understood, but host immunocompetence likely plays a role (Grogono‐Thomas et al. 2000; Grogono‐Thomas et al. 2003). In susceptible ewes, Campylobacter is no longer restricted in the gut and is able to translocate across the intestinal mucosa into blood circulation. This process results in bacteremia and dissemination of Campylobacter to the gravid uterus, where it causes placentitis, fetal infection, and abortion (Grogono‐Thomas et al. 2000; Grogono‐Thomas et al. 2003).

As shown in clinical cases and experimentally challenged animals, Campylobacter appears to show a fetoplacental tropism as large numbers of the organism can be detected in aborted placentas, fetal stomach contents, and fetal lung and liver (Sahin et al. 2008; Burrough et al. 2009; Burrough et al. 2012; Wu et al. 2016). Multiplication of Campylobacter in the fetoplacental unit triggers profound inflammation in the uteroplacental unit and fetal tissues, especially in the placenta (Sahin et al. 2008; Sanad et al. 2014; Yaeger et al. 2021). To investigate mechanisms of abortion, the gene expression of aborted placenta with Campylobacter infection was analyzed by microarray (Sanad et al. 2014) and RNAseq (Wu et al. 2019). Interestingly, the RNAseq study revealed a number of cytokine and cytokine receptor genes were upregulated in Campylobacter‐infected placentas compared with the non‐infected controls. Th1 cytokines, especially high levels of tumor necrosis factor α (TNFα), interferon γ, and IL‐2, are detrimental to pregnancy, inducing uterine contractions and damage to the fetoplacental unit (Entrican 2002). Both TNFα and interferon γ were significantly upregulated in Campylobacter‐infected sheep placenta. Thus, massive cytokine production and acute inflammatory response triggered by Campylobacter infection may directly contribute to abortion.

Both Cff and C. jejuni have some classical virulence attributes of bacterial pathogens, such as chemotaxis, motility, membrane surface structures, and adhesion to and invasion of host cells (Table 18.2; Blaser et al. 2008; Wu et al. 2013; Bolton 2015; Sahin et al. 2017b; Elmi et al. 2020; Kreling et al. 2020). Recently, small non‐coding RNA was also found to be involved in Campylobacter colonization of animals (Kreuder et al. 2020). However, specific virulence factors directly contributing to abortion pathogenesis are scarce. The surface of Cff is protected with S‐layer proteins (SLPs), noncovalently attached to the lipopolysaccharide (LPS). SLPs are highly antigenic, and exhibit high antigenic variations due to so called “nested DNA inversion” of the encoding sap genes (Dworkin and Blaser 1997). Mutant strains lacking SLPs lost the ability to cause abortion (Grogono‐Thomas et al. 2000), indicating that SLPs play an important function in Cff‐induced abortion. In vitro, SLPs have been demonstrated to confer resistance to complement‐mediated serum killing by preventing the binding of complement factor C3b (Thompson 2002; Blaser et al. 2008). In a mouse model with oral challenge, SLPs were shown to be critical for induction of bacteremia (Pei and Blaser 1990). Together, these findings suggest that SLPs contribute to the disease pathogenesis by allowing Cff to evade host immunity and survive in blood. However, it remains to be determined whether SLPs also play a role in pathogen–host interaction in the fetoplacental unit and whether they contribute to induction of proinflammatory responses.

C. jejuni lacks SLPs, but is covered with a layer of capsular polysaccharide (CPS) (Guerry et al. 2012). The structure of CPS is diverse in C. jejuni strains due to the variation in sugar compositions and glycan modifications (Guerry et al. 2012). CPS was shown to enable C. jejuni to resist complement‐mediated killing (Keo et al. 2011). The role of CPS in the abortion pathogenesis was recently evaluated using a mouse bacteremia model and a guinea pig abortion model using oral challenge (Sahin et al. 2017a). Without CPS, C. jejuni completely lost the ability to produce bacteremia in mice and abortion in guinea pigs. Compared with the wild‐type strain, the CPS‐deficient mutant was also severely compromised in serum resistance as determined with guinea pig sera and sheep blood. These findings indicated that CPS is a key virulence factor for systemic infection and abortion, probably by conferring resistance to complement‐mediated serum killing. However, CPS is ubiquitously present in C. jejuni isolates and it alone would not explain the hypervirulent property of C. jejuni clone SA in abortion induction. To elucidate what contributes to its hypervirulence, Wu and others designed a directed genome evolution strategy to identify the specific genetic elements that were required for the highly abortifacient phenotype of clone SA (Wu et al. 2016). Using this strategy and subsequent verification by gene‐specific mutation, the major outer‐membrane protein (MOMP) encoded by the porA gene was found to be essential for the hypervirulence phenotype of C. jejuni clone SA. Although MOMP is an essential protein in C. jejuni, it shows sequence polymorphisms among different strains, especially in the external loop regions (Wu et al. 2016). C. jejuni clone SA harbors unique amino acid polymorphisms in the predicted loop‐four region of MOMP, and the amino acid changes in this region convert a non‐abortifacient strain to a highly abortifacient strain (Wu et al. 2016), indicating they are functionally critical. Genomic analysis of historical isolates further revealed that MOMP sequence polymorphisms were involved in expansion of clone SA in the United States (Wu et al. 2016). How MOMP is involved in the pathogenesis of abortion is unknown and awaits further investigation.

Bovine Reproductive Loss

Cfv resides in the prepuce of bull without causing any clinical disease. The infection also does not compromise semen quality and breeding ability. When introduced into the genital of a naïve female, Cfv first establishes itself in the vagina during the luteal phase of the estrus cycle without further invasion (Seid 2019). This may be associated with the abundancy of neutrophils in the uterus during estrus, which limits the spread of Cfv

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