key: cord-335302-6wsx0jby
authors: Mahy, Brian W.J.
title: The diversity of viruses infecting humans
date: 2011-12-12
journal: Biodiversity (Nepean)
DOI: 10.1080/14888386.2006.9712792
sha: 
doc_id: 335302
cord_uid: 6wsx0jby

Most human viruses have been discovered through the diseases they cause in animals, plants, bacteria or fungi. Recent finds include human bocaviruses, which now seem to have a global distribution, and cause respiratory tract disease in infants, and several new pathogenic human coronaviruses. The SARS coronavirus, genetically distinct from all previously known coronaviruses, caused a disease which was highly transmissible and very severe, eventually leading to 8000 cases worldwide with over 800 deaths. Many viruses which are transmitted to humans by invertebrates, such as insects or ticks, have the ability to infect and replicate in cells of both vertebrate and invertebrate origin. However human virology is a rapidly expanding field and recent technologies such as the polymerase chain reaction (PCR) amplification system have made it possible to look for previously unrecognized viruses which may or may not be involved in pathogenesis. For example viruses in the genus Anellovirus are found in 80% of human blood samples yet do not seem to cause any disease. This paper overviews known human vertebrate viruses, more recent discoveries, and recommends a systematic search for viruses which may already infect the human population but have so far remained undetected.

The most recent report of the International Committee on Taxonomy of Viruses (ICTV) lists more than 6000 viruses that are classified into 1950 virus species and distributed among more than 391 different taxa (Fauquet et al. 2005) . In general, most of these viruses were discovered through the diseases they cause in animals, plants, bacteria or fungi, although since the development of the polymerase chain reaction (PCR) amplification system it has been possible to detect the presence of viruses that do not appear to cause any disease. An example of such viruses can be seen in the genus Anellovirus, which contains at least three small circular single-stranded DNA viruses that can be found in the blood of humans (Biagini et al. 2006) . These viruses are extremely widespread in the human population, with abundant anellovirus DNA being detectable in more than 80 % of human blood samples tested yet cause no clinical disease (Bendinelli & Maggi 2005) . For these reasons, any consideration of the diversity of human viruses must take into account that there has been no systematic search for human viruses that may or may not be associated with disease.

Humans are vertebrates, and the article by Craig Pringle in this issue ("The Taxonomy of Vertebrate Viruses") describes the many virus families and species known to infect vertebrates. Very few viruses are unique to the human species, and perhaps the only well known example, variola virus, has been eradicated by vaccination and now no longer exists in nature. Other potential targets for eradication, hepatitis C virus and human immunodeficiency virus (HIV) seem only able infect humans and certain non-human primates, but no vaccines have been developed so far that might prevent or eliminate these infections. It is also clear that many viruses which are transmitted to humans by invertebrates, such as insects or ticks, must have the ability to infect and replicate in cells of both vertebrate and invertebrate origin. Some of these, such as the flavivirus yellow fever virus, cause extremely serious disease consequences in humans, where they target liver cells, with replication in Kupffer cells, causing massive necrosis of hepatocytes which leads to jaundice and in the worst cases severe hemorrhagic fever involving the gastrointestinal tract. These pathological features made yellow fever one of the worst plagues in history, particularly affecting the African and South American regions, and perhaps because of the disease severity, the epidemiology of The diversity of viruses infecting humans Brian W.J. Mahy

Abstract. Most human viruses have been discovered through the diseases they cause in animals, plants, bacteria or fungi. Recent finds include human bocaviruses, which now seem to have a global distribution, and cause respiratory tract disease in infants, and several new pathogenic human coronaviruses. The SARS coronavirus, genetically distinct from all previously known coronaviruses, caused a disease which was highly transmissible and very severe, eventually leading to 8000 cases worldwide with over 800 deaths. Many viruses which are transmitted to humans by invertebrates, such as insects or ticks, have the ability to infect and replicate in cells of both vertebrate and invertebrate origin. However human virology is a rapidly expanding field and recent technologies such as the polymerase chain reaction (PCR) amplification system have made it possible to look for previously unrecognized viruses which may or may not be involved in pathogenesis. For example viruses in the genus Anellovirus are found in 80% of human blood samples yet do not seem to cause any disease. This paper overviews known human vertebrate viruses, more recent discoveries, and recommends a systematic search for viruses which may already infect the human population but have so far remained undetected. the disease was worked out and shown to involve mosquito borne transmission as early as 1900, when few viruses had been described (Reed 1902) . This led to the development of an effective attenuated yellow fever vaccine for the protection of humans. Unfortunately a satisfactory vaccine has not so far been developed for use against a related flavivirus, dengue/ dengue hemorrhagic fever virus, which occurs in four major antigenic types. But dengue fever virus, like yellow fever virus, is spread by Aedes aegypti mosquitoes, and so mosquito control methods have benefited the control of both these diseases.

In addition to insect borne flaviviruses, there are also serious diseases caused by tick borne flaviviruses, such as Kyasanur Forest disease virus, found in India, Omsk hemorrhagic fever virus, found in Russia, and Alkhurma hemorrhagic fever virus, found in Saudi Arabia. The exact mechanisms involved in the infection of insect cells versus tick cells or human cells are not well worked out, but it seems clear that viruses which alternate between infections of arthropod and vertebrate hosts show a remarkable genetic stability during experimental (Bilsel et al. 1988) or natural (Deubel et al. 1985; Charrel et al. 2005 ) transmission cycles.

Although human viruses have been studied for more than a century, it has become clear in the last 15 -20 years that a large number of new human virus infections have been newly recognized (Mahy and Murphy 2005) . In some cases a virus has been found in association with a long-recognized disease syndrome such as acute respiratory disease syndrome (ARDS) caused by the hantavirus Sin Nombre virus (Nichol et al. 1993) , and this led to the discovery of more than 30 related hantaviruses throughout the American continent. These virus infections are spread to humans through a vertebrate (usually a rodent) vector, but until the first one was recognized through epidemiological association and careful molecular analysis, they had remained unsuspected for decades.

Other new viruses have been recognized because of a new disease they caused in humans, such as the severe acute respiratory syndrome (SARS) coronavirus . The disease first appeared in humans in China in 2002, and by 2003 had spread to a number of neighbouring countries, The first virus isolate was made from samples taken from a physician who had died from the disease in Vietnam (Drosten et al. 2003; Ksiazek et al. 2003) . The unusual feature of the SARS coronavirus was that although previously known human coronavirus infections (human coronaviruses OC43 and 229E) had long been recognized as causing relatively mild symptoms such as the common cold, genetic analysis of the SARS virus showed that it was genetically distinct from all previously known coronaviruses, and caused a disease which was highly transmissible and very severe, eventually leading to 8000 cases worldwide with over 800 deaths. The coronaviruses are currently divided into three genetic groups, with human coronavirus 229E falling into group 1 and human coronavirus OC43 into group 2. Group 3 contains only avian coronavirus species. The sequence of the SARS coronavirus placed it in group 2 (Kim et al. 2006) . Studies on the origin of the SARS coronavirus are still ongoing: there is recent evidence of a zoonotic origin of the human disease, perhaps from palm civets, but the true natural reservoir of the virus seems most likely to be in a bat species, probably Chinese horseshoe bats (Lau et al. 2005; Li et al. 2005) .

What is clear, however, is that careful serological studies revealed no evidence of the presence of the virus in the human population before 2002 (Knobler et al. 2004) , when this virus first entered the human population and caused SARS.

In addition to SARS, which was the first major international disease outbreak of the 21 st century, a number of diseases of lesser importance have been newly recognized by the discovery of new virus species related to conventional virus infections. For example, it has been known for many years that the human parvovirus, a small single-stranded DNA virus known as B19, was the cause both of a rash in children called erythema infectiosum (fifth disease), and also of aplastic crisis in both children and adults with chronic hemolytic anemia. This was the only known human parvovirus until very recently, when a new parvovirus was discovered to be the cause of lower respiratory tract infections in children. The new virus was discovered by large-scale molecular virus screening of pooled human respiratory tract samples based on host DNA depletion, random PCR amplification, large-scale sequencing analysis and bioinformatics. This procedure detected one parvovirus and one coronavirus, both of which were at that time uncharacterized (Allander et al. 2005) . The human parvovirus displayed genome nucleotide sequence similarities to known parvoviruses infecting bovine and canine animal species, bovine parvovirus and canine minute virus, which had been placed in the genus Bocavirus of the subfamily Parvovirinae within the family Parvoviridae ( Fauquet et al. 2005 ). Thus the virus was provisionally named human bocavirus.

Surprisingly, studies carried out in Australia (Sloots et al. 2006 ) Japan (Ma et al. 2006 ) Canada (Bastien et al. 2006 ) and elsewhere (unpublished) have revealed a significant number of children whose lower respiratory tract disease appears to be caused by human bocavirus infection. The new human coronavirus detected by Allander et al. (2005) was found by sequence analysis to be related to another new human coronavirus identified in an elderly man who developed pneumonia in Hong Kong soon after returning from Shenzen, China (Woo et al. 2005a) . This virus was named human coronavirus-HKU1, since it was isolated in Hong Kong University. Further studies there showed that this virus was also associated with a second case of pneumonia, this time in a 35 year old woman, and a more complete investigation involving 4 hospitals showed that HCoV-HKU1 virus was responsible for 2.4% of all community-acquired pneumonia (Woo et al. 2005b) . Most recently, HCoV-HKU1 virus was found in Australian children (Sloots et al. 2006) , and in 5 children and one adult in Caen, France (Vabret et al. 2006 ).

Probably as a result of the sudden world-wide interest in human coronaviruses generated by the discovery of the SARS coronavirus, other new human coronaviruses were found using more conventional approaches. In 1994, a group from the University of Amsterdam isolated a new coronavirus from a 7month-old child suffering from bronchiolitis and conjunctivitis, and named the virus HCoV-NL63. The virus was genetically distinct from previously reported coronaviruses, but appeared to be a new group 1 coronavirus which was widely spread in the Dutch population ( (Kaiser et al. 2005) and China (Chiu et al. 2005; Zhu et al. 2006) .

At the same time that the Amsterdam group were reporting their findings, a group at Yale university discovered a closely related if not identical coronavirus to NL63 which they named New Haven coronavirus (HCoV-NH) (Esper et al. 2005a ). The Yale group admitted that their coronavirus was similar and might represent the same species as HCoV-NL63. However, in an accompanying paper, Esper et al. (2005b) went on to claim an association between HCoV-NH and Kawazaki disease, a childhood systemic vasculitis long suspected of having a viral origin, though none has ever been found. The importance of this claim stimulated existing Kawasaki research groups in California and in Taiwan to look for the virus in their clinical specimens, but neither group could confirm any association of either HCoV-NH or HCoV-NL63 with the disease (Shimizu et al. 2005; Chang et al. 2006 ).

It is clear from these recent discoveries that the SARS epidemic catalyzed a great deal of excellent work in what had been a neglected area of virology with the result that we now have more than doubled the number of known human coronaviruses from 2 to at least 5. How many more might still be undetected?

In their seminal paper describing the discovery of the new human parvovirus, human bocavirus, Allander et al. (2005) suggest that it might be possible to undertake a systematic exploration to describe the "human virome". This might be based not on disease, but given our extensive data bank of virus sequences, it would be possible to carry out a systematic search for the presence of viruses in human tissues. The coronaviruses were investigated because of the intense interest in understanding SARS and its origins, but I suggest that an alternative approach might be to focus on viruses known to be important causes of disease in animals, but for which a persistent lifelong infection with no obvious pathological consequences apart from a tenfold rise in lactate dehydrogenase enzyme in the blood. But in aging mice of certain strains a form of poliomyelitis may develop. All arteriviruses, including LDV, primarily infect macrophages. The only known primate arterivirus affects monkeys, causing simian hemorrhagic fever.

Finally, in addition to the coronavirus genus, the family Coronaviridae includes the genus Torovirus, whose members are known to infect horses, bovines and carnivores. The discovery of at least one human torovirus has recently been claimed and linked to neonatal necrotizing enterocolitis (Lodha et al. 2005) .

There is no doubt that human virology is a rapidly expanding field, and technological advances have now made it possible to look for previously unrecognized viruses existing in the human population which may or may not be involved in pathogenesis. Recent examples of such newly recognized viruses include the human bocaviruses, which now seem to have a global distribution, causing respiratory tract disease in infants, and several new pathogenic human coronaviruses, As we continue to search for the causes of many human diseases of unknown aetiology, it may be prudent to undertake a more systematic search for viruses which may already infect the human population but have so far remained undetected.

Cloning of a human parvovirus by molecular screening of respiratory tract samples

New human coronavirus, HCoV-NL63, associated with severe lower respiratory tract disease in Australia

Human coronavirus NL63 infection in Canada

Human bocavirus infection

Human coronavirus NL63 infections in children: a 1-year study

of Topley&Wilson's Microbiology and Microbial Infections

Identification of a third member of the Anellovirus genus ("small anellovirus") in French blood donors

RNA genome stability of Toscana virus during serial ttransovarial transmission in the sandfly Phlebotomus perniciosus

Lack of association between infection with a novel human coronavirus (HCoV), HCoV-NH, and Kawasaki disease in Taiwan

Low diversity of Alkhurma hemorrhagic fever virus, Saudi Arabia

Human coronavirus NL63 infection and other coronavirus infections in children hospitalized with acute respiratory disease in Hong Kong

Homogeneity among Senegalese strains of yellow fever virus

Identification of a novel coronavirus in patients with severe acute respiratory syndrome

Detection of human coronavirus NL63 in young children with bronchiolitis

Evidence of a novel human coronavirus that is associated with respiratory tract disease in infants and young children

Association between a novel human coronavirus and Kawasaki disease

Virus Taxonomy, Eighth Report of the International Committee on Taxonomy of Viruses

Human coronavirus NL63 associated with lower respiratory tract symptoms in early life

Close relationship between SARS-coronavirus and group 2 coronavirus

Learning from SARS. Preparing for the next disease outbreak

A novel coronavirus associated with severe acute respiratory syndrome

Severe acute respiratory syndrome coronavirus-like virus in Chinese horseshoe bats

Bats are natural reservoirs of SARSlike coronaviruses

Human torovirus: a new virus associated with neonatal necrotizing enterocolitis

Detection of human bocavirus in Japanese children with lower respiratory tract infections

of Topley&Wilson's Microbiology and Microbial Infections

A novel pancoronavirus RT-PCR assay: frequent detection of human coronavirus NL63 in children hospitalized with respiratory tract infections in Belgium

Genetic identification of a hantavirus associated with an outbreak of acute respiratory illness

Recent researches concerning etiology, propagation and prevention of yellow fever by the United States Army Commission

Lactate dehydrogenaseelevating virus

Human coronavirus NL63 is not detected in the respiratory tracts of children with acute Kawasaki disease

Evidence of human coronavirus HKU1 and human bocavirus in Australian children

Detection of the new human coronavirus HKU1: a report of 6 cases

Identification of a new human coronavirus

Characterization and complete genome sequence of a novel coronavirus, coronavirus HKU1, from patients with pneumonia

Clinical and molecular epidemiological features of coronoavirus HKU1-associated community-acquired pneumonia

Human coronavirus NL63 was detected in specimens from children with acute respiratory infection in Beijing, China