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BackgroundDengue virus type 3 genotype III (DENV3/III) is associated with increased number of severe infections when it emerged in the Americas and Asia. We had previously demonstrated that the DENV3/III was introduced into Malaysia in the late 2000s. We investigated the genetic diversity of DENV3/III strains recovered from Malaysia and examined their phylogenetic relationships against other DENV3/III strains isolated globally.ResultsPhylogenetic analysis revealed at least four distinct DENV3/III lineages. Two of the lineages (DENV3/III-B and DENV3/III-C) are current actively circulating whereas the DENV3/III-A and DENV3/III-D were no longer recovered since the 1980s. Selection pressure analysis revealed strong evidence of positive selection on a number of amino acid sites in PrM, E, NS1, NS2a, NS2b, NS3, NS4a, and NS5. The Malaysian DENV3/III isolates recovered in the 1980s (MY.59538/1987) clustered into DENV3/III-B, which was the lineage with cosmopolitan distribution consisting of strains actively circulating in the Americas, Africa, and Asia. The Malaysian isolates recovered after the 2000s clustered within DENV3/III-C. This DENV3/III-C lineage displayed a more restricted geographical distribution and consisted of isolates recovered from Asia, denoted as the Asian lineage. Amino acid variation sites in NS5 (NS5–553I/M, NS5–629 T, and NS5–820E) differentiated the DENV3/III-C from other DENV3 viruses. The codon 629 of NS5 was identified as a positively selected site. While the NS5-698R was identified as unique to the genome of DENV3/III-C3. Phylogeographic results suggested that the recent Malaysian DENV3/III-C was likely to have been introduced from Singapore in 2008 and became endemic. From Malaysia, the virus subsequently spread into Taiwan and Thailand in the early part of the 2010s and later reintroduced into Singapore in 2013.ConclusionsDistinct clustering of the Malaysian old and new DENV3/III isolates suggests that the currently circulating DENV3/III in Malaysia did not descend directly from the strains recovered during the 1980s. Phylogenetic analyses and common genetic traits in the genome of the strains and those from the neighboring countries suggest that the Malaysian DENV3/III is likely to have been introduced from the neighboring regions. Malaysia, however, serves as one of the sources of the recent regional spread of DENV3/III-C3 within the Asia region.Electronic supplementary materialThe online version of this article (10.1186/s12862-018-1175-4) contains supplementary material, which is available to authorized users.

Dengue virus type 3 genotype III (DENV-3/III) is widely distributed in most dengue-endemic regions. It emerged in Malaysia in 2008 and autochthonously spread in the midst of endemic DENV-3/I circulation. The spread, however, was limited and the virus did not cause any major outbreak. Spatiotemporal distribution study of DENV-3 over the period between 2005 and 2011 revealed that dengue cases involving DENV-3/III occurred mostly in areas without pre-existing circulating DENV-3. Neutralisation assays performed using sera of patients with the respective infection showed that the DENV-3/III viruses can be effectively neutralised by sera of patients with DENV-3 infection (50% foci reduction neutralisation titres (FRNT50) > 1300). Sera of patients with DENV-1 infection (FRNT50 ⩾ 190), but not sera of patients with DENV-2 infection (FRNT50 ⩽ 50), were also able to neutralise the virus. These findings highlight the possibility that the pre-existing homotypic DENV-3 and the cross-reacting heterotypic DENV-1 antibody responses could play a role in mitigating a major outbreak involving DENV-3/III in the Klang Valley, Malaysia.