【病毒外文文献】2006 [Perspectives in Medical Virology] Emerging Viruses in Human Populations Volume 16 __ Severe Acute Respiratory Synd

insights into processes of molecular emergence Global research efforts are con tinuing to increase our understanding of the virus the pathogenesis of the disease it Kong on February 21 2003 and from there to other parts of the world A week later Carlo Urbani Reilley et al 2003 an Italian infectious disease expert work ing in the Hanoi Vietnam office of the WHO responded to a possible avian influenza alert from French Hospital That action by one man set into motion the engagement of the WHO emergency measures by the Vietnamese government and eventually the attention of the world In Geneva WHO team member Klaus Sto hr The beginning of the epidemic and the identification of SARS CoV The epidemic began in Guangdong province China in late 2002 It spread to Hong causes SARS the heterogeneity of individual infectiousness described below as well as shedding light on how to prepare for other emerging viral diseases Promising drugs and vaccines have been identified The milestones achieved have resulted from a truly international effort Tommy R Tong Department of Pathology Princess Margaret Hospital Laichikok Kowloon Hong Kong China Severe acute respiratory syndrome SARS caused by a coronavirus CoV SARS CoV emerged into human populations in south China Anon 2003d Peiris et al 2003b c Poon et al 2004a from bats Guan et al 2003 Kan et al 2005 Lau et al 2005 Li et al 2005d Normile 2005 in late 2002 Subsequently SARS CoV that had adapted to humans caused an epidemic in 29 countries and regions to which it had been carried by airline passengers The epidemic was controlled by public health measures coordinated by the WHO and on July 5 2003 it was of ficially declared to have ended Because of these public health measures a pan demic was averted Enserink 2003b Close to 10 of the 8000 persons infected in this epidemic died Molecular studies dissected the adaptation of this virus as it jumped from an intermediary animal the civet to humans giving us valuable Emerging Viruses in Human Populations Edward Tabor Editor r 2007 Elsevier B V All rights reserved DOI 10 1016 S0168 7069 06 16004 8 43 Severe Acute Respiratory Syndrome Coronavirus SARS CoV T R Tong44 Stafford 2005 put together and maintained a network of 11 microbiology labo ratories in nine countries to respond to the epidemic and to identify the etiologic agent Anon 2003b Early encounters with SARS in Hong Kong suggested that a virus may have been the cause of the illness Tsang et al 2003a Early candidate agents suggested were a paramyxovirus and a coronavirus as well as the bacterial agent Chlamydia pneumoniae Stadler et al 2003 In the last week of March 2003 laboratories in Hong Kong China the United States and Germany isolated a novel coronavirus from clinical material obtained from patients with SARS Drosten et al 2003a Ksiazek et al 2003 Peiris et al 2003b Serological studies and RT PCR specific for this coronavirus subsequently called SARS CoV were positive in most prob able SARS patients but not in controls RT PCR products of several specimens from different geographical locations had identical nucleotide sequences support ing the existence of a point source outbreak No other potential agent was con sistently identified SARS CoV could be grown in cell culture in Vero African green monkey kid ney cells Drosten et al 2003b Ksiazek et al 2003 and FRhK 4 fetal Rhesus kidney cells Peiris et al 2003b The Hong Kong group led by Malik Peiris Peiris 2003 was the first to observe the cytopathic effect of the virus seen after 2 4 days of incubation consisting of cell rounding refractile appearance and detachment The initial cytopathic effect was sometimes delayed until 6 days post inoculation Drosten et al 2003a More recently a clone of persistently infected Vero E6 cells has been established Yamate et al 2005 Work at Hong Kong University and the U S Centers for Disease Control and Prevention CDC resulted in the identification of the virus causing SARS The CDC workers were the first to visualize the characteristic morphology of SARS CoV in infected cells and in culture supernatant using transmission electron microscopy with negative staining Fig 1 which they shared with the network laboratories within 24h Anderson 2005 With that information the CDC suc cessfully probed the virus with group I coronavirus polyclonal antibodies and employed primers IN 2 IN 4 C0 that targeted a conserved region of the co ronavirus polymerase gene open reading frame ORF 1b thus amplifying the corresponding genomic region of SARS CoV Rota et al 2003 Microarray hybridization further confirmed that the agent was a coronavirus In Hong Kong differential display priming between SARS CoV infected and uninfected cell cul tures and cloning were used to show that the virus was a coronavirus Peiris et al 2003b German researchers performed random priming utilizing degenerate bases followed by sequencing and translated BLAST search to identify the RT PCR products as those of a coronavirus Drosten et al 2003a Definitive proof of SARS CoV as the etiologic agent of SARS came when Rotterdam virologists led by Albert Osterhaus Enserink 2003a produced data that fulfilled Koch s last postulates Macaque monkeys Macaca fascicularis de veloped a SARS like illness after experimental infection yielded the same virus inoculated and developed a specific antibody response Fouchier et al 2003 Severe Acute Respiratory Syndrome Coronavirus SARS CoV 45 Fig 1 Electron micrograph of SARS CoV The virus measures 60 120nm in size See text for descrip tion Image generously provided by CDC C D Humphrey and T G Ksiazek US CDC Website http www cdc gov ncidod sars lab images htm Kuiken et al 2003 Co infection of macaques with human metapneumovirus hMPV a virus that had earlier been a candidate agent for the cause of SARS was not associated with more severe illness Fouchier et al 2003 hMPV infection without SARS CoV caused only minor upper respiratory illness in adults Ksiazek et al 2003 although hMPV alone can cause severe pneumonia in young children van den Hoogen et al 2001 SARS CoV was deemed necessary and sufficient to cause SARS On April 16 2003 David Heymann 2004 Executive Director WHO Com municable Diseases programs Klaus Sto hr and Albert Osterhaus announced that SARS was caused by the novel coronavirus SARS CoV Anon 2003b and they dedicated the work to Dr Urbani who died from SARS that he had contracted while caring for patients in Vietnam The epidemic timeline and highlights SARS was notorious for a high incidence of acute respiratory distress and respi ratory failure a significant death rate even in healthy young adults Lee et al 2003b Tsang et al 2003a a high rate of nosocomial transmission Booth et al 2003 and superspreading events SSE Lai et al 2004 Shen et al 2004 Lloyd Smith et al 2005 Galvani and May 2005 Fig 2 The epidemic in China almost became a pandemic when a physician guest at the Hotel Metropole Hong Kong who had been infected while treating SARS patients in Guangzhou unknowingly Humanization of SARS CoV late October mid November 2002 SARS outbreak in Guangzhou China mid November 2002 SARS arrived in Hong Kong and two days later in Singapore and Toronto Feb 21 2002 SARS arrived in Vietnam from Hong Kong Carol Urbani consulted Feb 28 2003 Carlo Urbani dies March 29 2003 Amoy Gardens Hong Kong outbreak WHO recommends global port screening of travelers April 2 2005 WHO issues global alert following outbreaks in Vietnam and Hong Kong March 12 2003 SARS outbreaks in Hong Kong Beijing Toronto Singapore March 2003 WHO global network born Mar 17 2002 March 21 2003 US CDC preliminary description of SARS SARS CoV identified by Hong Kong US CDC China s Vice Premier Wu Yi commands the battle against SARS in China SARS outbreak in Taiwan China completed a new1 000 bed infectious disease hospital Xiaotangshan in 8 days 229 3947 deaths cases Chinese and Hong Kong researchers found SARS CoV in wild animals in Guangdong markets May 23 2003 WHO begins removing cities regions from travel alert Outbreaks in satellite cities around Guangzhou city Guangdong province China late October 2002 WHO removes last region Taiwan from list of travel alert July 5 2003 and declares end of human to human transmission Four cases reported in Guangzhou city Dec 20 2003 not linked to laboratory http www who int csr don 2004 01 05 en Scientist in Singapore gets SARS from laboratory http www who int csr don 2003 09 24 en index html Senior scientist in Taiwan gets SARS from laboratory http www who int csr don 2003 12 17 en index html Dec 31 2003 Transmission on aircraft Mar 15 2002 Postgraduate student in Beijing gets SARS from laboratory and initiated three generations of transmission in a total of 8 cases with one fatality Scientist in Beijing gets SARS from the same laboratory in April 2004 http www who int csr don 2004 04 30 en index html 774 8096 deaths cases HKU virologist Yi Guan traveled to China to obtain clinical specimens Fig 2 Timeline of the SARS epidemic Major events are listed from top to bottom Each interval in the arrow represents 1 week For information on the first weeks of the epidemic in China consult the book by Thomas Abraham Twenty First Century Plague The Story of SARS The Johns Hopkins University Press Baltimore Maryland 2005 For colour version see Colour Section on page 348 T R Ton g 46 Severe Acute Respiratory Syndrome Coronavirus SARS CoV 47 introduced SARS CoV into Hong Kong on February 21 2003 He was probably a superspreader and Hong Kong became ground zero However in most other places where SARS CoV spread the chain of trans mission stopped promptly with the isolation of patients According to the Basic Reproductive Number R 0 arrived at by averaging the number of infections pro duced by infected individuals in susceptible populations SARS was not as con tagious as influenza R 0 2 7 Riley et al 2003 and 5 25 respectively However this simplification ignores a property of certain infectious diseases including smallpox influenza and SARS called the heterogeneity of individual infectious ness Highly variable infectiousness means that some infected individuals may cause explosive transmissions giving rise to SSEs During the SARS epidemic a spectrum of infectiousness was seen that included SSEs uneventful terminations of transmission chains and explosive outbreaks Galvani and May 2005 Lloyd Smith et al 2005 SSEs likely require high levels of viral shedding and others factors which together determine the Individual Reproductive Number Lloyd Smith et al 2005 One of these factors might be production of a large amount of bioaerosol by certain individuals Edwards et al 2004 Reducing bioaerosol by inhalation of nebulized saline Edwards et al 2004 and or the use of cough suppressants could impact the Individual Reproductive Number and reduce the occurrence of SSEs Another cofactor might be a pneumonic phase with airborne dissemination of the virus Lloyd Smith et al 2005 Because infectious disease agents exist as quanta and not as plasma airborne dissemination is difficult to prove owing to the stochastic process involved in the distribution of viruses by aerosol During the Toronto portion of the SARS epidemic investigations using state of the art air sampling devices confirmed the presence of SARS CoV in the air of a patient s room Booth et al 2005 These studies together with data from investigation of transmission on aircraft Olsen et al 2003 and the huge out break of SARS in Amoy Gardens Hong Kong Yu et al 2004b showed that SARS CoV is an opportunistic airborne pathogen Roy and Milton 2004 Hav ing recognized that airborne dissemination of SARS CoV is the route of trans mission facilities can be upgraded with impact on other airborne infectious diseases as well The high incidence of nosocomial transmission of SARS CoV during the epi demic exposed a weakness in the infection control procedures in some locations as medical workers became vectors for SARS CoV Meng et al 2005 but did not occur everywhere Seto et al 2003 Multiple layers of defense are needed as Chowell et al have suggested because using their model for R 0 25 of their R 0 distribution lies at R 0 1 even with perfect isolation Chowell et al 2004 Helpful measures might include the avoidance of crowding in clinics and wards wearing face masks Seto et al 2003 avoiding aerosolizing procedures if possible Tong et al 2003 Tong 2005b improved ventilation design and rate Liao et al 2005a and making sure that there are no weak links in infection control T R Tong48 Emergence and origin of SARS CoV The theory that SARS CoV came from an animal reservoir gained credence when field investigations by WHO showed that significant numbers of early patients were food handlers Anon 2003c Normile and Enserink 2003 Xu et al 2004c Yi Guan and others investigated food markets in Guangdong where a variety of small animals were kept in unhygienic heaped up cages prior to sale Guan et al 2003 SARS CoV like coronaviruses were promptly identified in several Himalayan palm civets Paguma larvata and one raccoon dog Nyctereutes procyonoides Anti bodies against SARS CoV were also found in market workers The relationship between these isolates from animals and isolates from humans appeared to be the result of a one way transmission from animals to humans because a 29 nucleotide deletion was found in the strain of SARS CoV isolated from humans compared with civet SARS CoV it is easier to lose nucleotides than to gain some Chinese 2004 Kan et al 2005 Song et al 2005b Genomic comparisons further suggested that SARS CoV was unlikely to be a recombinant between human and animal coronaviruses or between various animal coronaviruses ruling out natural or lab oratory chimerism Holmes and Rambaut 2004 Thus SARS CoV was probably a zoonotic virus Holmes 2003 Zhong et al 2003b It was also found that civets make a good amplification reservoir because SARS CoV genomic RNA persisted in the spleen and lymph nodes of civets for as long as 35 days Wu et al 2005b Diversity of SARS CoV genomes among human isolates was greatest in Guangdong agreeing with animal studies that suggested south China was the site of emergence of the virus Guan et al 2004 Moreover humanization likely occurred in a person of recent southern Chinese ancestry because indigenous Tai wanese with their distant HLA Class I genes have been shown to be significantly less susceptible to SARS than residents of Taiwan who are immigrants from mainland China Lin et al 2003b It is believed that the humanization of SARS CoV occurred only a few weeks before the epidemic of SARS in China The estimated dates of interspecies leap based on mutational analyses in both Singapore and China are in remarkably close agreement late October 2002 and mid November 2002 respectively Chinese 2004 Vega et al 2004 The estimated mutation rates were 5 7C210 C06 nucleotides per site per day in a Singapore isolate and 8 26C210 C06 in a China isolate again in remarkable agreement with each other and with the rate of 1 83C210 C06 in a Taiwan isolate Yeh et al 2004 This rate of mutation is among the slowest in RNA viruses Retrospective seroepidemiological studies confirmed that SARS CoV did not begin circulating in humans until recently Only 1 8 of 938 sera collected in Hong Kong in May 2001 Zheng et al 2004b none of 60 sera collected in Guangdong in early 2003 Zhong et al 2003b and 1 minimal reactivity on ELISA of 384 sera from U S blood donors contained antibodies against SARS CoV Ksiazek et al 2003 Zheng et al 2004b When quantified titers of antibodies in these early sera were higher against civet SARS CoV than against human isolates of SARS CoV Zheng et al 2004b Severe Acute Respiratory Syndrome Coronavirus SARS CoV 49 However farmed civets elsewhere in China were mostly negative for SARS CoV Tu et al 2004 so the hunt for the natural reservoir continued Taking clues from other zoonotics scientists turned to bats as a possible animal reservoir since bats have been shown to be a reservoir for rabies virus Ebola virus Hendra virus Menangle virus and Nipah virus Dobson 2005 Leroy et al 2005 In 2005 two independent groups published definitive findings on the bat as a natural reservoir of SARS CoV Kwok yung Yuen discovered three novel coro naviruses in different species of bat including one virus with 88 nucleotide identity with SARS CoV a virus that they named bat SARS CoV Lau et al 2005 Poon et al 2005 Bat SARS CoV found in the insectivorous Chinese horseshoe bat Rhinolophus sinicus is nearly identical to civet SARS CoV including pres ervation of a 29 nucleotide segment not found in the majority of human isolates of SARS CoV Also nearly identical to civet SARS CoV is SL CoV Rp3 and perhaps related strains Rp1 and Rp2 found in Rhinolophus pearsoni by Li et al 2005d Shi Zhang and Wang s Sino Australian cooperative effort also involving Hong Kong University produced proof that the bat is the natural reservoir for the SARS CoV like coronaviruses These findings will lead to vaccines and drug treat ments for SARS Dobson 2005 Because SARS CoV appears to jump species easily more wildlife reservoirs of SARS CoV may be discovered Macaques domestic cats ferrets raccoon dogs pigs and even mice are known to be susceptible to SARS CoV infection Fouchier et al 2003 Martina et al 2003 Wentworth et al 2004 Chen et al 2005b Li et al 2005d Nevertheless the fact that bats roost in large colonies makes them ideal reservoirs to maintain viruses and other microorganisms Normile 2005 In addition bats are in the same Mammalia Class as humans so viruses of bats will not require great changes to infect human cells Li et al 2005e After the epidemic was declared over four small subsequent outbreaks oc curred Three were the result of SARS CoV escaping from the laboratory by infecting personnel as David Ho had predicted might occur Enserink 2003c and has occurred with Russian influenza in 1977 Horimoto and Kawaoka 2005 The fourth case was a form fruste reemergence in the epicenter of the original outbreak Guangzhou between December 2003 and January 2004 Enserink 2004 Liang et al 2004 Normile 2004 Song et al 2005b In this reemergence four people developed SARS and were confirmed to have SARS CoV by RT PCR Three had had direct or indirect contact with palm civets and one lived near a hospital that earlier admitted many patients with SARS All recovered and seroconverted Amplified sequences of the viruses isolated from them were very similar to those of SARS CoV found in the preceding winter in caged animals Chinese 2004 Song et al 2005b The one patient in the reemer gent outbreak who had had no contact with civets had earlier disposed of a dead rat leading health officials of Guangdong to trap rodents near his residence some of the rats Rattus rattus were found to have SARS CoV in feces and lung tissue http www egms de en meetings sars2004 04sars023 shtml though not overtly ill T R Tong50 The virus Taxonomy and phylogeny SARS CoV belongs to the family Coronaviridae which are enveloped RNA viruses in the order Nidovirales Cavanagh 1997 Coronaviruses are classified into three serogroups Viruses in groups 1 and 2 are mammalian viruses group 3 contains only avian viruses Human coronaviruses HCoV are found in both group 1 HCoV 229E and HCoV NL63 and group 2 HCoV OC43 and CoV HKU1 and are responsible for 30 or more of generally mild upper respiratory tract illnesses To position SARS CoV Snijder et al used a rooted phylogenetic tree that included an outgroup the equine torovirus EToV Snijder et al 2003 They concluded that SARS CoV is distantly related to established group 2 coronaviruses agreeing with Peiris s phylogenetic analysis using the polymerase gene Peiris et al 2003b Most of the genome of SARS CoV is closely related to group 2 coronaviruses Magiorkinis et al 2004 Now SARS CoV is placed in a new subgroup 2b with the other group 2 coronaviruses assigned to a new subgroup 2a Stadler et al 2003 Gorbalenya et al 2004 In addition bat SAR