NC1202: Enteric Diseases of Food Animals: Enhanced Prevention, Control and Food Safety
Statement of Issues and Justification
NEEDS. The long-term goal of this collaborative project is to prevent and control enteric diseases of cattle, swine and chickens with a mandate to decrease food and waterborne illness in the USA. Foodborne illness has been a prominent public health concern for over two decades yet the Centers for Disease Control (CDC) still list many enteric foodborne pathogens as leading causes of morbidity and mortality in the US. Despite many concerted efforts to use hygiene and sanitation measures to control these pathogens in food animals pre- and postharvest, incidence of many food and waterborne pathogens remains high and some are increasing. Nevertheless, a broad range of educational, scientific and practical controls have succeeded in decreasing the incidence of five key foodborne pathogens. Over the last 10 years, our enteric diseases group has been a part of that effort and we are dedicated to prevent and control animal and human disease due to enteric pathogens. Our collaborative efforts harmonize with national efforts established this year under the FDA Food Safety Modernization Act to ensure the US food supply is safe by shifting the focus of federal regulators from responding to contamination to preventing it. A main avenue for prevention is decreasing carriage and disease due to enteric pathogens in food animals.Foodborne outbreaks. Foodborne illness is a major public health concern in the US due to the occurrence of many large-scale outbreaks with intense media scrutiny(9). From 2009 to 2011, outbreaks of Salmonella occurred from exposures to animal products (Italian style meats, ground turkey, bologna, shell eggs), produce (alfalfa sprouts, cantaloupes, fresh papayas, pistachios), processed foods (peanut butter, frozen entrees, frozen fruit pulp), animals (ducklings, frogs, chicks), restaurant chains, and microbiology laboratories. These included many strains of Salmonella including: Enteritidis, Chester, Typhi, Hartford, Baildon, Newport, Montevideo, Typhimurium, Heidelberg, Agona, Altona, Johannesburg, Hadar, Panama, Saintpaul and several untyped Salmonella. Outbreaks of disease due to Shiga toxin-producing (STEC) E. coli have also occurred during this time after exposures to beef, Lebanon bologna, cheese, prepackaged cookie dough, romaine lettuce, hazelnuts, and travel to Germany. In these outbreaks, strain types were mainly STEC E. coli O157:H7 but, non-O157 strains e.g.O104 also caused outbreaks. Other multistate foodborne outbreaks included Listeria linked to cantaloupes and Campylobacter linked to raw milk. Most exposures involved contaminated meats, milk or cross contamination of other foods from meat or animals. Moreover, the strain diversity and allelic variation expressed by bacterial isolates from these outbreaks demonstrates the complexity of sources contributing to these problems.
Sporadic foodborne illness. In 1995, improved surveillance for foodborne illness was instituted when Food-Net was established; this is a collaborative program among CDC, 10 state health departments, USDA FSIS, and FDA. Food-Net conducts surveillance for bacterial (Campylobacter, Listeria, Salmonella, STEC E. coli O157 and non-O157, Shigella, Vibrio, and Yersinia) and parasitic (Cryptosporidium, Cyclospora) infections diagnosed by laboratory testing of patient samples. Initial work by Food-Net demonstrated a huge US burden of disease with >75 million cases of foodborne illness annually, resulting in 325,000 hospitalizations and 5,000 deaths. By 2011, FoodNet reports 48 million illnesses, 128,000 hospitalizations, and 3,000 deaths annually from foodborne infections. Despite encouraging declines, annual rates of disease due to enteric pathogens are high: Campylobacter (2 million cases), Salmonella (1.4 million cases), STEC E. coli O157 and non-O157 (73,480 cases), Listeria (2,797 cases), Shigella (1,780 cases), Vibrio (193 cases), Yersinia (159 cases), Cryptosporidium (1,290 cases), and Cyclospora (28 cases)(58). It is not surprising that the President, Congress, and USDA have made food safety a high priority. Statistics from FoodNet surveillance highlight three main points: 1) Most food-borne illness events are of undefined etiology, stressing the need for identification and characterization of novel, emerging, or previously unrecognized agents. Recent recognition of norovirus induced food and waterborne illness is a striking reminder that agents of major importance can go unrecognized for years. 2) Most of the known bacterial, viral and parasitic foodborne disease agents are primarily zoonotic. Thus, investigation and control in animal reservoirs are required to understand their epidemiology and biology to maximize opportunities for control. 3) Several of these agents are also severe pathogens of animals or have close relatives that are animal pathogens. Thus, investigation of the host-parasite relationship in animal models or in animal populations could solve these problems in humans.
Chronic disease. While most foodborne pathogens cause acute disease, many of them can cause severe complications or chronic diseases. Severe manifestations include hemorrhagic colitis, septicemia, meningitis, joint infection, hemolytic uremic syndrome with kidney failure, paralysis and miscarriage, among other diseases. Autoimmune disorders are rapidly increasing in incidence(3) and a number of these syndromes are documented to be triggered by enteric pathogens. For example, C. jejuni is a leading cause of bacterial gastroenteritis that can trigger serious autoimmune diseases. The acute neuropathies Guillain Barré Syndrome and Miller Fisher Syndrome, and Inflammatory Bowel Disease and Reiters Arthritis have all been associated with recent Campylobacter infection(44).
Waterborne illness. The CDC, EPA, and Council of State and Territorial Epidemiologists run the Waterborne Disease and Outbreak Surveillance System for collecting and reporting data on waterborne disease outbreaks associated with drinking and recreational water(72). A report from 2005-2006 showed 78 waterborne disease outbreaks in 31 states with 4,412 persons affected resulting in 116 hospitalizations and five deaths. 61% of these were enteric illness with the majority caused by parasites, viruses and bacteria. The agents of highest prevalence were Cryptosporidium, Vibrio, Campylobacter and Naegleria. Conclusions were that there was a substantial increase in number of recreational water-associated diseases and outbreaks compared to previous years. Recent increases in disease in marine animals exposed to ground water runoff containing animal and human enteric pathogens points out the need to manage both human and animal wastes(63). A major long-term goal of our group is to implement strategies derived from basic research efforts to control microbial contamination of water resources and provide a safe and sustainable environment for animal production facilities. Based on CDC estimates, enteric caliciviruses (Noroviruses, Sapoviruses) cause over 9 million cases of foodborne illnesses yearly, making them the most common cause of acute foodborne gastroenteritis in the US(40). Recently, caliciviruses that are genetically more closely related to human caliciviruses than to other animal caliciviruses have been identified in fecal samples from swine and cattle(10, 11, 23, 36, 60, 66, 68-70). Moreover, shellfish approved for human consumption contain both animal and human enteric caliciviruses(10).
Food animals harbor enteric pathogens. STEC. Cattle are important reservoirs of E. coli O157:H7 because the organism colonizes the colon without causing disease and exhibits a tissue tropism for the rectum of adult cattle(46, 55). In contrast, other serotypes (O5, O26, O111) colonize the entire large intestine of young calves(61). Intestinal colonization by E. coli O157:H7 and other EHEC requires the formation of A/E lesions, mediated through proteins secreted by a type III secretion system and the outer membrane protein known as intimin(12, 41, 47, 52, 67). Colonization of the colon in cattle results in shedding of the organism in feces(41, 54, 62). Control of fecal shedding of E .coli O157:H7 by cattle and other animal reservoirs is imperative since it represents the primary contamination source of food and water and can also infect humans via direct contact(1, 15, 62). Although post-harvest interventions have been implemented and significantly reduced E. coli O157 contamination of ground beef(2), the organism is still highly prevalent in US cattle and pre-harvest interventions are needed to reduce carriage levels(7, 33).
ETEC. Enterotoxigenic E. coli cause diarrhea in neonates (piglets, calves and lambs) and young animals (piglets) by adhering to intestinal epithelial cells and producing enterotoxin(45). ETEC cause death of 10.8% of all pre-weaning pigs and 1.5-2% of all weaned pigs(25, 65). Incidence of neonatal diarrhea has been reduced substantially using vaccines, but post-weaning ETEC diarrhea remains economically significant for the swine industry. Common ETEC diarrheal strains in piglets produce K88 (F4) or F18 fimbriae(18). These fimbriae bind to glycoconjugates that serve as receptors in porcine enterocyte brush borders. Absence of the respective glycoconjugate renders animals resistant to bacterial colonization and diarrheal disease(16, 17, 19). ETEC strains produce several types of enterotoxins, including heat labile enterotoxin (LT), heat stable enterotoxin-a (STa), heat stable enterotoxin-b (STb)(45), and enteroaggregative E. coli produce heat stable enterotoxin 1(39, 57, 71). ETEC must produce both enterotoxin and fimbriae in order to cause severe dehydrating diarrheal disease(4, 19, 59). Piglet enterocyte susceptibility to K88+ ETEC adherence is inherited in a simple Mendelian fashion as a dominant trait, and susceptibility to K88+ ETEC mediated disease correlates with expression of an intestinal mucin-type glycoprotein receptor for K88+ fimbria(19, 22). K88+ ETEC strains are extremely virulent because of high intestinal colonization, severe dehydrating diarrhea, post-diarrheal septicemia, and death(42). Post-diarrheal septicemia involves the development of severe dehydration, hypovolemic shock, and ischemia of the intestinal mucosa(4, 42).
Salmonella. Foods of animal origin are commonly contaminated with Salmonella spp. including the food animals that we study (cattle, swine, chickens). Salmonella enterica is a common cause of systemic and diarrheal disease in livestock with economic losses estimated to be $12 billion; it causes ~2 million cases of diarrhea per year in humans in the US with up to 1000 deaths. Many strains of Salmonella have recently emerged. In 2000-2005, the CDC noted a rapid increase in laboratory confirmed Salmonella Newport infections (126%). Concern was raised because: 1) the spectrum of illness due to this serovar tends to be more severe, and 2) an increasing number of Newport isolates are multi-drug resistant. Multi-drug resistance prevalence increased from 1% in 1998 to 26% in 2001, with some isolates being resistant to ceftriaxone, a drug commonly used to treat invasive Salmonella infections. The emergence of a multi-drug resistant S. Newport was attributed to various factors including intensive farming practices, movement of cattle between farms and overuse of antimicrobial agents on dairy operations(24).
Campylobacters. Incidence of foodborne disease due to C. jejuni remains very high worldwide; chicken is the most common source(20, 28). Yet, a recent study showed using multilocus sequence typing that water and milk are commonly contaminated with C. jejuni and that sporadic infections in humans may arise from sources other than chickens(32). It is well known that cattle and swine shed C. jejuni, C. coli and often other campylobacters at slaughter. Raw milk from dairy cattle has caused outbreaks of C. jejuni enteritis (29, 30, 50); recent molecular testing showed C. jejuni, E. coli, Salmonella Typhimurium, Listeria and Yersinia in raw milk(21). Besser et al showed transmission of C. jejuni among feedlot cattle during the feeding period that resulted in a high prevalence of excretion of this pathogen by cattle slated to go to slaughter (5). Unfortunately, chlorination of water did not decrease this problem. C. jejuni has also been associated with weaning age diarrhea in swine(35, 56). Pigs harbor both C. coli and to a lesser extent C. jejuni, but recent data show that both cause human enteritis; in fact C. coli predominates as a cause in some regions and other campylobacters can also causes disease(53, 64). Another growing problem is the increasing prevalence of antibiotic resistant campylobacters. A disturbing trend is that enhanced fitness in the host was observed for fluoroquinolone-resistant C. jejuni in the absence of antibiotic selection pressure(34). So, despite the removal of fluoroquinolones as feed additives for chickens, this antibiotic resistance has persisted and increased.
Lawsonia. Proliferative enteropathy (ileitis) is a common enteric disease of weaned pigs and other animals caused by an intracellular bacterium, L. intracellularis(37). Infections are common and estimates of annual economic losses are ~$100 million for the US swine industry(38). Clinical signs include diarrhea, weight loss, and melena(38).Characteristic lesions in all species are marked proliferation of immature epithelial cells in crypts of the ileum or colon, or both, leading to thickening and branching of crypts and gross mucosal thickening with intracellular bacteria(38). Little is known of the pathogenesis and sensitive and specific methods for diagnosis are not universally available. Genomic characterization of the organism will help to identify genes responsible for virulence and to develop diagnostic reagents and recombinant vaccines. A molecular typing database will enable studies on ecology and epidemiology of L. intracellularis.
Spirochetes. Advances in phenotypic and genotypic characterization of pig intestinal spirochetes have increased our understanding of swine dysentery (SD) and porcine colonic spirochetosis (CS) caused by Brachyspira hyodysenteriae and Brachyspira pilosicoli, respectively(26, 27, 51). SD has devastating economic impacts on pig production, but changes in management designed to eliminate SD has produced a declining prevalence in US swine. Yet, in most pig producing countries SD continues to be a major health challenge. In contrast, porcine CS, a less severe form of diarrheal disease of grower pigs, has become more widely recognized. While SD is restricted to pigs and rodent vectors, CS affects a wide range of hosts including human and non-human primates, dogs, horses, and birds(13, 14, 43). Although limited epidemiological investigations suggest a zoonotic potential with public health significance for B. pilosicoli (6, 48, 49), the role of this spirochete in human colitis is uncertain.
Cryptosporidium. Cryptosporidium is the most common enteric pathogen of calves and is responsible for significant economic losses to the dairy and cattle industries. It is also a significant threat to water resources and human health. In 1991, a National Dairy Heifer Evaluation Project indicated that this parasite was present on more than 90% of farms surveyed, with 22% of pre-weaned heifers shedding oocysts on any given day. A single calf can excrete up to 10 7 oocysts per gram feces. Damage to host intestinal epithelium during infection results in a decrease in absorptive surfaces, gut mucosal inflammation, secretion of electrolytes into the lumen, and persistent diarrhea. In 2011, there are no effective treatments for humans or livestock with Crypto.
IMPORTANCE & CONSEQUENCES. In 2000, USDA ERS estimated $6.9 billion/year for medical costs, productivity losses, and costs of premature deaths for diseases caused by five common foodborne pathogens.
Besides human health risks, animal diarrheal disease due to food-safety related pathogens and other animal-specific pathogens remain an economically important cause of production loss to livestock producers. Recent surveys from NAHMS and the National Pork Producers Council indicate the continuing importance of enteric diseases as major sources of morbidity, mortality, and economic costs. The cost of just E. coli O157:H7 to the beef industry from 1993-2003 was estimated at $2.671 billion(31). The 2000 National Water Quality Inventory reports that agricultural non-point-source pollution is the leading source impacting water quality in surveyed rivers and lakes. It is also a major contributor to ground water contamination, wetlands degradation and human illness from waterborne pathogens. Yet, Food-Net indicates significant progress in control of illness caused by Campylobacter, Salmonella, E. coli, Listeria, Cryptosporidium and Yersinia. These declines are the result of diverse actions such as pre- and post-harvest interventions and education of producers and consumers. While the incidence of disease caused by some of these agents approaches 2010 targets, rates can be further reduced with new knowledge and new detection procedures developed through this collaborative research. As production systems for food animals evolve toward larger sizes and complexity, antibiotics in feed become banned and natural, grass-fed, and organic production systems emerge and expand, continued research in support of food safety and control of diarrheal diseases of livestock is needed to optimize animal health and welfare and to produce safe foods. Consequences of inaction are increases in disease and costs.
FEASIBILITY. Progress has been made in preventing and controlling foodborne illness. A recent report by CDC based on 1996-2010 data concluded that the incidence of several high impact pathogens has declined based on targeting them for control and prevention(8). Declines in incidence occurred in Campylobacter, Listeria, STEC O157, Shigella, and Yersinia infection, while Salmonella and Vibrio increased. CDC believes this success demonstrates the feasibility of preventing foodborne illnesses; research, collaboration and dissemination of successful innovations will be important to continue this trend.
MULTISTATE EFFORTS. The magnitude of this problem dictates a team-based approach to devising and implementing preventatives. People with markedly varied areas of expertise are needed to devise scientific strategies for pathogen control, for education of agricultural experts and producers and for applying the strategies on farms. The complexity and range of these enteric pathogens and of the food animal production systems in which they occur require collaborative research involving scientists with a wide range of expertise to work together in pursuit of solutions. No individual institution can match the range of scientific expertise we offer. The NC-1041 group has bacteriologists, virologists, molecular biologists, pathologists, and immunologists with a history of collaboration and productivity in developing innovative strategies.
IMPACTS, INNOVATION, OUTCOMES. 1)Emerging diseases. We expect to identify, characterize and develop improved detection and prevention methods related to newly recognized, novel or emerging causes of zoonotic enteric disease and enteric pathogens of food animals. 2)Developing preventions & interventions. We expect to develop and improve preventative measures and interventions to reduce the incidence and prevalence of infections of food animals with enteric and foodborne pathogens. 3)Disseminating knowledge. We will provide training or continuing education to disseminate new information to students, producers, veterinarians, diagnostic labs and others to implement interventions and preventative measures. Expected outcomes will be increased understanding of mechanisms of initiation of acute and chronic enteric infections for known and emerging enteric pathogens. This will provide science-based best practices and implementation strategies for preventive measures and interventions for the major enteric diseases of food animals. The new NC-1041 project addresses critical cross-cutting research areas and objectives that will enhance food safety while maintaining efficient pork, beef and chicken production.
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