key: cord-252103-lsaa1nx0
authors: Pearks Wilkerson, Alison J; Teeling, Emma C; Troyer, Jennifer L; Bar-Gal, Gila Kahila; Roelke, Melody; Marker, Laurie; Pecon-Slattery, Jill; O'Brien, Stephen J
title: Coronavirus outbreak in cheetahs: Lessons for SARS
date: 2004-03-23
journal: Current Biology
DOI: 10.1016/j.cub.2004.02.051
sha: 
doc_id: 252103
cord_uid: lsaa1nx0

nan

comparative insight into the prospects for a coronavirus-based epidemic [6] . The affected animals died of feline infectious peritonitis (FIP), caused by a feline coronavirus (FCoV, also called FIPV). The presence of a cheetah coronavirus (Aju-CoV, for Acinonyx jubatus coronavirus) was inferred based upon the presence of FIPV antibodies and the observation of coronavirus-like particles [6, 7] . In domestic cats FCoV occurs in two varieties: virulent FIPV which causes severe FIPV antibody mediated fatal disease in about 5-10% of infected cats, and a subclinical enteric feline coronavirus (FECV) infection. Within months of arrival of the two infected cheetahs to Winston Safari, other cheetahs in the park fell ill. Retrospective serum samples tested for antibodies demonstrated that prior to 1982 all cheetah serum were negative, but within six months of the Sacramento cheetahs' arrival, 100% of the cheetahs had seroconverted, most with titers >1600 (Supplemental Figure S1 ). Ninety percent of the 60 cheetahs in the park developed disease symptoms including jaundice, diarrhea, weight loss, gingivitis, hepatic and renal pathology. With a mortality of 60% within 2-3 years, this was the most extreme outbreak of coronavirus in any species recorded.

To characterize the genomic disposition of the cheetahs' Aju-CoV strain, PCR primers based on alignment of seven coronavirus gene segments (pol1a, pol1b, S, M, N, 7a/7b, and 3′ ′UTR), were used to amplify cDNA from archived cheetah liver and kidney tissues collected during the Winston outbreak. Tissues from five different cheetahs were successfully used for amplification of 439 bp of the pol 1b gene, 405 bp of pol 1a, 316 bp of N-7a, and 187 bp in the 3′ ′UTR region. Phylogenetic analyses of aligned virus genome sequences confirm the monophyly of three previously discovered antigenic groups of coronavirus, plus the divergent SARS-CoV genome (Figure 1 and Supplemental Data). The cheetah isolates were nested within a group of domestic cat viruses using pol 1a, N-7a and also in a polyphyletic intermix with the 3′ ′UTR gene segment. The phylogenetic analyses indicate a close similarity of the Aju-CoV and the FCoV strains, suggesting the cheetah virus is closely related to, if not indistinguishable from, domestic cat isolates. The most likely scenario to explain these results is that FCoV jumped from the domestic cat into the cheetah. Interestingly, the two cheetahs exported from Sacramento to Winston had visited the U.C. Davis veterinary hospital, where many domestic cat FCoV isolates were originally isolated, suggesting an opportunity for cross species transmission.

Second, in cats, cheetahs and humans, the viruses are highly contagious, spreading rapidly through close quarters in weeks, if not days. Third, despite these similarities, there is a clear difference in age sensitivity. For SARS, there were virtually no childhood cases, and the mortality reaches over 50% in people over 65 or with pre-existing medical complications [8] . In cheetahs and domestic cats, mortality is the highest in neonates, infants or subadults; 85% of cheetah cubs succumbed to the Winston outbreak [6] . Fourth, while mortality among humans with SARS symptoms and house cats with FCoV is low, around 5-10%, cheetahs with Aju-CoV exhibited the opposite extreme, showing 90% morbidity and over 60% mortality.

There are two plausible explanations for the cheetah's extreme sensitivity to Aju-CoV. One is that slight mutational differences transform a relatively benign coronavirus strain to a virulent 'hot' strain. Among coronaviruses this scenario has been proposed, but not proven, for the transition of FECV to FIPV in cats [9]. This hypothesis is less likely for the cheetahs, as in the outbreak mentioned above lions became infected concurrently with the cheetahs, but developed no overt symptoms [6] . Also, experimental transmission of the Aju-CoV to three domestic kittens failed to cause disease [6] . Perhaps also relevant is that when the human SARS-CoV was induced in domestic cats, they developed no symptoms [4] .

Cheetahs are known as the world's fastest land animal but also for their extreme genetic uniformity, a consequence of their escape from extinction some 12,000 years ago. Remarkably, unrelated cheetahs accept skin grafts from nonrelatives, a characteristic of highly inbred laboratory strains of mice or rats [8] . The most likely explanation for the high mortality in cheetahs is their genetic uniformity, particularly at immune genes like the MHC. This may have rendered the species susceptible to an emerging virulent strain that had evolved to circumvent the defenses of the first victim. If this hypothesis is correct, the greater genetic diversity of domestic cats and humans may reduce the severity of the epidemic, and also contribute to the occurrence of rare genetically determined SARS-CoV super-spreaders who can infect with high virulence. This explanation emphasizes the critical role of intrinsic genomic diversity among immune defense genes in any fatal epidemic. As such, the search for explicating genetic susceptibility polymorphisms that may inform prognosis, spread therapy, and prevention of emerging pathogens seems warranted, particularly to anticipate future episodes of the deadly SARS coronavirus. 

Revised U.S. surveillance case definition for severe acute respiratory syndrome (SARS) and update on SARS cases -United States and worldwide

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Genetic basis for species vulnerability in the cheetah

Prevalence and implications of feline coronavirus infections of captive and freeranging cheetahs (Acinonyx jubatus)