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UniProt release 2018_01

Published January 31, 2018

Zika virus: from petty crime to banditry

A Zika virus (ZIKV) outbreak in Brazil in 2015 drew the world’s attention to this microbe (see UniProt headline). The situation was so severe that in February 2016 it was declared to be a ‘public health emergency of international concern’ by the World Health Organization (WHO), indicating that it constituted a public health risk to other States through the international spread of the disease and potentially required a coordinated international response.

ZIKV has been known for over 70 years since its first isolation from a febrile rhesus macaque in the Ugandan Zika forest. The clinical symptoms caused by ZIKV infection in humans were mild at that time, consisting of a self-limiting flu-like febrile illness that resolved within days and occurred in an estimated 20% of infected individuals. The picture of the recent epidemic was however dramatically different. ZIKV infection was associated with severe symptoms, including multi-organ failure. The most alarming feature was its ability to cause microcephaly, congenital malformations, and fetal demise in pregnant women.

When did the metamorphosis from an almost innocuous agent to a congenital pathogen with global impact occur? In the decades following its discovery, sporadic human ZIKV infections were reported in a few countries in Africa, and then the virus started spreading, first to Southeast Asia, to Micronesia in 2007, to French Polynesia in 2013-2014, and soon after to South and Central America. Comparison of ZIKV neurovirulence between ‘ancestral’ (African/Southeast Asian) and ‘contemporary’ (Polynesian/South American) strains was done by intracerebral injections of the virus in neonatal mice. All 3 contemporary strains led to 100% mortality, with typical neurological manifestations. By contrast, the ‘ancestral’ strain killed less than 17% of the animals. Moreover in a mouse embryonic microcephaly model, infection with a ‘contemporary’ ZIKV strain resulted in brains exhibiting a substantial degree of microcephaly contrary to the ancestral strain which caused less severe symptoms. Both viruses targeted neural progenitor cells, but the ‘contemporary’ strain showed significantly enhanced replication in the brain compared with the ‘ancestral’ one. Obviously something had changed between the ‘ancestral’ ZIKV and its ‘contemporary’ version, something that boosted ZIKV neurovirulence, but what?

This question was addressed by Yuan et al. Sequence alignments between ‘ancestral’ (INSDC accession number AY632535) and ‘contemporary’ (KJ776791) strains show many differences at the amino acid level. To find out which changes account for increased neurovirulence, several ‘contemporary’ strain-specific substitutions were introduced in the ‘ancestral’ strain and tested in neonatal mice. One of them, the substitution of a serine residue by an asparagine at position 139 (in the precursor polyprotein), S139N, greatly increased the neurovirulence of the ancestral strain. It also showed enhanced replication in neural progenitor cells and caused more extensive cell death compared with the original ‘ancestral’ virus. Conversely, when this residue was mutated back to serine in the ‘contemporary’ strain, mortality caused by the ‘contemporary’ virus in neonatal mice was significantly decreased. The ZIKV S139N substitution probably emerged in May 2013, a few months before the outbreak in French Polynesia, and was then stably maintained in the epidemic strain during its subsequent spread to the Americas. Its emergence correlates with reports of microcephaly and other severe neurological abnormalities.

After maturation of the genome polyprotein, position 139 is found in viral protein prM, which, in flaviviruses, closely associates with the envelope protein E and is believed to prevent premature fusion of immature virions inside infected cells. However, the mechanism through which the S139N substitution increases neurovirulence is not yet known.

At the beginning of 2016, UniProtKB/Swiss-Prot released the annotated sequence of a ZIKV genome polyprotein, corresponding to the East African ‘ancestral’ strain. In order to meet the needs of the scientific community, we have now released that of a ‘contemporary’ strain, isolated from a French Polynesian sample.

Changes to the controlled vocabulary for PTMs

New terms for the feature key ‘Modified residue’ (‘MOD_RES’ in the flat file):

  • S-carbamoylcysteine
  • S-cyanocysteine