Novel coronavirus lab studies hint at wide tissue susceptibility

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Mar 27, 2013 (CIDRAP News) – Experiments by Hong Kong researchers to gauge the susceptibility of several human and animal cell lines to novel coronavirus (NCoV) found signs that it can infect a broad range of tissues, which might shed light on the disease's seemingly high mortality rate.

Though many questions remain about the source of the new virus and how it spreads, health officials know that it can cause severe clinical illness in some patients, including severe pneumonia and renal failure, the group wrote. They added that until more is known about the disease, lab studies could help provide clues.

The tests they conducted with NCoV and the cell lines are surrogates of virus growth in the tissues. They measured viral load in the cultures, nucleoprotein expression, and cytopathic effect. They published their findings yesterday in an early online edition of the Journal of Infectious Diseases (JID).

The group used an autopsy NCoV virus sample obtained from the first known case-patient, a Saudi Arabian man who died from the disease in June. They used 27 cell lines from different tissues and organs in their susceptibility tests, 14 from humans and 13 from animals.

Tests suggested that NCoV can infect human respiratory, kidney, and liver cells, as well as histiocytes. The impact on neuronal cells and monocytes was much less.

Researchers suggested that the range of human tissues that are susceptible to infection appears to be broader than all other human coronaviruses, including the SARS (severe acute respiratory syndrome) virus. The team said this finding might help explain the disease's pathogenesis and high mortality.

Human upper-airway cells did not seem to support the growth of the novel virus, which the investigators said isn't surprising, given that many of the lab-confirmed cases had severe acute pneumonia. However, more data on infected patients is needed to determine if the clinical pattern is similar to SARS, in which the virus was also shed in the upper airways, which played a role in human-to-human transmission.

More studies are needed to explore the histopathologic changes in the kidneys of patients infected with NCoV, the group wrote. They also noted that research is needed to determine the viral load in patients' urine specimens, because acute renal failure might be a mortality risk factor for NCoV, as it was for SARS.

Experiments on the animal cell lines suggested that NCoV can infect cells from non-human primates, pigs, civets, and rabbits, results that they said add to earlier findings showing the virus can infect bat cells. They wrote that their findings strengthen the suspicion that the virus can jump interspecies barriers.

"The presence of a receptor utilized by the virus which is common in bats, primates, pigs, civets, rabbits, and humans might imply a broad species tropism, which is unique among all the currently known human coronaviruses," the group wrote.

In an editorial in the same issue of JID, Kenneth McIntosh, MD, with the division of infectious Diseases at Boston Children's Hospital, wrote that aside from extensive genetic sequence data and a report on receptor usage in tissue culture, little has been published on the biology or pathogenicity of NCoV in humans or animals.

McIntosh noted that in the current study infectious virus wasn't measured in any of the cell lines and that evidence of viral replication was measured more indirectly, based on detection of viral RNA or viral nucleoprotein.

Though virologists have used in vitro tests to guide them oin what cells to tests for in vitro growth and understanding more about pathogenesis, he wrote that there are several examples, including those involving coronaviruses, in which viruses didn't behave as expected in the organisms.

Filling knowledge gaps about NCoV based on in vitro tests is tempting, but difficult and risky, McIntosh wrote. However, he added that the Hong Kong group's work is useful for showing wide tissue tropism in the lab.

ECDC airs geographic considerations
In other developments, the European Centre for Disease Control and Prevention (ECDC) updated its epidemiologic assessment today, as four new cases have been reported since its last report on Feb 22.

It noted that three of the four cases were reported by Saudi Arabia's health ministry, with the last one reported on Mar 25 by Germany's Robert Koch Institute, the 73-year-old man from the United Arab Emirates who died in a Munich hospital yesterday.

The ECDC noted that six case-patients so far have been diagnosed and treated in Europe, three of whom were transferred from Arabian Peninsula countries where they were infected.

Though the number of NCoV infections increased over the past month, most cases continue to have links to the Arabian Peninsula, where contact tracing and epidemiologic investigations are under way, the group wrote.

Also, the ECDC issued a separate document that addresses the World Health Organization's (WHO's) NCoV surveillance update, which was published on Mar 18. Though the latest version from the WHO is more comprehensive, the ECDC took issue with one of the testing recommendations.

It noted that for testing, the WHO no long distinguishes between countries in which unexplained sporadic cases have occurred and those, such as in Europe, that have detected imported cases or infections linked to imported cases.

It said the November version of the WHO guidance specifically referenced countries in the Arabian Peninsula and their neighbors. However, the ECDC said it and the US Centers for Disease Control and Prevention (CDC) are retaining that recommendation. The CDC lists the countries considered in the Arabian Peninsula and neighboring areas as Bahrain, Iraq, Iran, Israel, Jordan, Kuwait, Lebanon, Oman, Palestinian territories, Qatar, Saudi Arabia, Syria, the United Arab Emirates, and Yemen.

"In ECDC's view, at present there is not a case for considering European countries epidemiologically the same as those countries in the Middle East where indigenous sporadic infections and clusters have been detected," the statement says.

The ECDC added that a strong case can be made for EU countries to continue using geography as one risk factor for testing patients for NCoV and for healthcare workers to remain vigilant when caring for patients with respiratory infections who are evacuated from Arabian Peninsula and neighboring countries.

Chan JF, Chan K, Choi GK, et al. Differential cell line susceptibility to the emerging novel human betacoronavirus 2c EMC/2012: implications on disease pathogenesis and clinical manifestation. J Infect Dis 2013 Mar 26 [Abstract]

McIntosh K. A new virulent human coronavirus: how much does tissue culture tropism tell us? (Editorial) J Infect Dis 2013 Mar 26 [Full text]

See also:

Mar 27 ECDC epidemiological update

Mar 27 ECDC public health development document

CDC novel coronavirus case definition

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