JPC SYSTEMIC PATHOLOGY

DIGESTIVE SYSTEM

August 2024

D-B07

 

Signalment (JPC #1214032): Juvenile rhesus monkey (Macaca mulatta)

 

HISTORY: This monkey had intractable diarrhea.

 

HISTOPATHOLOGICAL DESCRIPTION: Colon: Diffusely, and most severely over Peyer’s patches, there is partial to full thickness mucosal necrosis and ulceration with abundant hemorrhage, fibrin, eosinophilic cellular and karyorrhectic debris, intact and ruptured neutrophils and scattered superficial colonies of mixed rods and cocci. Occasionally, remaining intestinal crypts are ectatic, lined by attenuated epithelium, and contain sloughed epithelial cells admixed with ruptured neutrophils (crypt abscesses). The gut associated lymphoid tissue (GALT) contains decreased numbers of lymphocytes and increased numbers of tingible body macrophages admixed with eosinophilic cellular and karyorrhectic debris (lymphoid depletion). Within the area of lymphoid depletion there is herniation of crypts through the muscularis mucosa (crypt herniation). Multifocally, blood vessels in the lamina propria and submucosa are variably occluded by finely fibrillar to polymerized to hyalinized eosinophilic fibrin admixed with enmeshed degenerative inflammatory cells (fibrin thrombi). Diffusely, the submucosa is moderately expanded by increased clear space with ectatic lymphatics (edema) and finely beaded eosinophilic fibrin admixed with moderate numbers of neutrophils and fewer lymphocytes and plasma cells, and multifocal mild hemorrhage. 

 

MORPHOLOGIC DIAGNOSIS: Colon: Colitis, necrohemorrhagic, acute, diffuse, severe, with fibrin thrombi, lymphoid depletion, edema, and crypt herniation. Rhesus monkey (Macaca mulatta), nonhuman primate.

 

ETIOLOGIC DIAGNOSIS: Colonic shigellosis

 

ETIOLOGY: Shigella spp.

 

CONDITION: Bacillary dysentery

 

GENERAL DISCUSSION: 

• Gram-negative, nonmotile, non-spore forming, aerobic and facultative anaerobic rod-shaped bacteria
• Shigella spp. cause dysentery in non-human primates (NHPs) and in humans, mainly affecting the cecum and large intestines (small intestines are not affected)
• Four serogroups (all are enteroinvasive): 
  • S. dysenteriae
  • S. flexneri 
  • S. boydii 
  • S. sonnei
• One of the most common enteric infection in NHPs (mainly Old World monkeys [OWM])
  1. Agent is acquired in captivity through association with human caretakers and may become endemic in colonies
• S. flexneri and S. sonnei are endemic & cause majority of all infections in humans and NHPs; S. dysenteriae is the most pathogenic (Shiga toxin)
• Few organisms are required to cause disease

 

PATHOGENESIS: 

• Fecal-oral transmission > enter M (microfold) cells through a phagosome > lyse phagosome and proliferate intracellularly > transmigrate into lymphoid follicles > phagocytized by macrophages > macrophage apoptosis > induction of IL-8 > neutrophil recruitment and mucosal inflammation > inflammatory response damages integrity of epithelial lining > luminal bacteria directly invade epithelial cells > bacterial invasion of enterocytes at basolateral surface (preferred invasion site) > bacterial replication in the cytoplasm of enterocytes > spread via F-actin microfilaments (intracellular) and pseudopods (extracellular) > widespread colonic epithelial damage
• Asymptomatic carriers/shedders important in propagation of disease; animals can be chronically re-infected
• Toxins: Both chromosomal and plasmid encoded gene expression are required for full virulence expression; toxins delivered via a type III secretion system that injects bacterial proteins directly into host cell cytoplasm

• S. dysenteriae – Shiga toxin (highly cytotoxic via inhibition of protein synthesisàcell death)
  • Damages endothelium in microvasculature of colon and glomeruli
  • Can lead to hemolytic-uremic syndrome in humans
• S. flexneri – produces cytotoxin (kills host cell) and enterotoxin (fluid secretion by small intestine)
• All Shigella spp. produce Shigella toxin (binds to a membrane glycolipid receptor)

 

TYPICAL CLINICAL FINDINGS:

• Incubation of 1-4 days
• Watery and/or mucoid, bloody diarrhea; lethargy; dehydration; edema of face and neck; and weight loss
• Most commonly associated with reactive arthritis (stifle, elbow, coxofemoral, and interphalangeal joints)
• Acute cases are often fatal 
• May be asymptomatic (i.e. carriers)

 

TYPICAL GROSS FINDINGS: 

• Affects terminal ileum, cecum, colon and rectum
  • Necrohemorrhagic colitis, 
  • +/– ulceration with pseudomembrane formation
  • Edema 
• Mesenteric lymphadenopathy
• Possible sequela include small intestinal intussusception or rectal prolapse
• May cause necrohemorrhagic periodontitis/gingivitis and arthritis

 

TYPICAL LIGHT MICROSCOPIC FINDINGS: 

• Necrotizing colitis, mucosal edema, congestion, hemorrhage, necrosis, with possible ulceration and pseudomembrane formation, often over or adjacent to Peyer’s Patches
• Blood vessels in mucosa and submucosa are congested and may contain fibrin thrombi
• Large numbers of neutrophils and fewer lymphocytes, plasma cells, and macrophages invade mucosa
• Mucosal crypt abscesses and crypt herniation into the GALT may be present

 

ULTRASTRUCTURAL FINDINGS:

 

ADDITIONAL DIAGNOSTIC TESTS: 

 

DIFFERENTIAL DIAGNOSIS:

Gross and microscopic findings:

• Campylobacter fetus ssp. jejuni and E. coli affect both small and large intestine; lesions are less severe than those of Shigella spp.; both are associated with chronic colitis of macaques
• Salmonella enteritidis or typhimurium causes necrotizing, suppurative enterocolitis and can cause septicemia
• Yersinia enterocolitica and Y. pseudotuberculosis produce submucosal microabscesses with large colonies of bacteria
• Enteropathogenic (or enteroinvasive) E. coli causes hemorrhagic gastroenteritis and ulcerative colitis
• Balantidium coli can cause ulcerative colitis
• Stress, dietary changes, and inflammatory bowel disease

 

COMPARATIVE PATHOLOGY: 

• Primarily NHP and human disease
• High zoonotic potential 
• Dogs can be transient excreters due to coprophagia

 

REFERENCES: 

1. Simmons J, Gibson S. Bacterial and Mycotic Diseases of Nonhuman Primates. In: Abee CR, Mansfield K, Tardif S, et al. Nonhuman primates in biomedical research: Diseases. Vol 2. San Diego, CA: Academic Press; 2012: 136-138.
2. Brady AG, Carville AL. Digestive System Diseases of Nonhuman Primates. In: Abee CR, Mansfield K, Tardif S, et al. Nonhuman primates in biomedical research: Diseases. Vol 2. San Diego, CA: Academic Press; 2012: 591, 599-600. 
3. Brogden KA. Cytopathology of pathogenic prokaryotes. In: Cheville NF, ed. Ultrastructural pathology: The comparative cellular basis of disease. 2nd ed. Danvers, MA: Wiley-Blackwell; 2009: 474-475. 
4. Greene C. Shigellosis. In: Greene C, ed. Infectious diseases of the dog and cat. 4th ed. St. Louis, MO: Saunders; 2012: 389-390
5. Lowenstine LJ, Mcmanamon R, Terio KA. Chapter 15: Apes. In: Terio KA, McAloose D, St. Leger J, ed. Pathology of Wildlife and Zoo Animals, Cambridge, MA Academic Press; 2018: 395.
6. Matz-Rensing K, Lownestine LJ. Chapter 14: New World and Old World Monkeys. In: Terio KA, McAloose D, St. Leger J, ed. Pathology of Wildlife and Zoo Animals, Cambridge, MA Academic Press; 2018: 356-357.
7. Turner JR. The gastrointestinal tract. In: Kumar V, Abbas AK,, Aster JC, Turner JR eds. Robbins and Cotran: Pathologic Basis of Disease. 10th ed. Philadelphia, PA: Elsevier; 2021: 790-791
8. Uzal FA, Plattner BL, Hostetter JM. Alimentary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. 6th ed. Vol 2. Philadephia, PA: Elseveier; 2016:, 158, 162, 166. 

 

 

Click the slide to view.

---