OVERVIEW

Arthropod-borne viruses (arboviruses) constitute one of the most significant emerging disease challenges to global public health. The escalating pandemic of dengue virus, the recent invasion of West Nile virus into the Americas, and the persistence of yellow fever virus in the tropics all attest to the threat posed by arboviruses, particularly flaviviruses (genus Flavivirus, family Flaviviridae). Our research uses techniques from both molecular and classical virology, as well as entomology, to investigate the emergence, evolution and epidemiology and control of flaviviruses. We focus on mosquito-borne dengue virus, the causative agent of dengue fever.

Research in the Hanley lab is supported by grants and fellowships from NIH-NM-INBRE (P20-RR016480-05), NIH-K22 (K22-A164193), NSF-ADVANCE (SBE-123690) and RISE (NIH grant GM61222).

PEOPLE

• KATHRYN HANLEY
• TAMMY ROMERO
• EBENEZER TUMBAN
• SWATI MUKHERJEE
• NYREE MAES
• MICHEAL McDOWELL
• KALLI LAMBETH
• GONAZALO CASTILLO
• CHRIS HERRERA
• RYAN McNAMARA

PROSPECTIVE STUDENTS

I encourage students with an interest in doing research at the interface between evolutionary ecology and molecular virology to consider joining the lab.

SPECIFIC PROJECTS

I. Mechanisms for competitive displacement among strains of dengue virus

Ecologists have had a longstanding interest in the mechanisms of competitive displacement, the removal of one species from a location or habitat by a second species, because of the impact of invasive species on native communities. However competitive displacement is also an important process in disease emergence. The displacement of a low virulence strain of pathogen by a high virulence strain can result in an increase in disease severity, one of the hallmarks of emergence. Competitive displacement among different virus strains is an increasingly common feature of dengue virus epidemiology. We are currently investigating the mechanisms that may contribute to such displacement, including: (i) exploitation competition, the monopolization of human hosts by one virus strain due to an advantage in transmission over other strains, (ii) direct competition, the suppression of replication of one strain by a second strain during co-infection, and (iii) apparent competition, the generation of an immune response by one strain that is more damaging to co-infecting competitors than to self.

NIH collaborators: Steve Whitehead, Chris Hanson
and Joe Blaney



II. Barriers to emergence of sylvatic dengue viruses

Among the arthropod-borne viruses, dengue virus, which infects 100 million people per year, is the most pressing threat to global public health. Endemic dengue viruses circulate exclusively between humans and peridomestic Aedes mosquitoes and thus are a potential target for eradication. However, an additional reservoir of dengue virus exists: sylvatic dengue viruses that circulate between non-human primates, and possibly other reservoir hosts, and sylvatic species of Aedes. The four serotypes of endemic dengue virus have emerged from these sylvatic ancestors in four independent events. Given the propensity of sylvatic viruses for emergence, it is critical to assess the risk that they pose to contemporary human populations. With our collaborators at University of Texas Medical Branch and Institut Pasteur, we have tested the hypotheses that sylvatic dengue viruses lack infectivity for either humans or peridomestic mosquitoes and that adaptation to one or both of these hosts would be required to enable emergence. Neither hypothesis was supported (Vasilakis et al. 2007; Hanley et al. manuscript in preparation), and currently we are investigating the role of competition between endemic and sylvatic lineages in the exclusion of sylvatic lineages from circulation in humans.

Collaborators: Amadou Sall (Institut Pasteur), Scott Weaver (Univ. Texas), Doug Watts (UT), and Mawlouth Diallo (IP)

 

III. Vector-driven selection in dengue virus

At present, neither a licensed vaccine nor anti-viral drugs are available to control dengue disease. To design such measures requires a detailed understanding of the adaptation and current function of the virus genome. My lab is contributing to this effort through a variety of projects, described below:

(i) Incorporation of deletions into the 3’ untranslated region of the genome of dengue virus has been a promising approach for the development of vaccine candidates. Such deletions alter both primary sequence and secondary structure of this region. While the incorporation of a 30-nucleotide deletion (∆30) into dengue virus serotypes 4 and 1 has resulted in vaccine candidates rDEN4∆30 and rDEN1∆30, currently in clinical trials, incorporation of ∆30 into dengue serotype 3 did not attenuate this virus. With our collaborators at NIAID, my lab is currently investigating the impact of ∆30 on the secondary structure of dengue virus, using computer-generated predictions of structure coupled with nuclease mapping. These data will enable us to better understand the variation in the phenotypic impact of ∆30 and to design strategies for developing a dengue serotype 3 vaccine (Romero et al. 2006, Blaney et al. submitted to Vaccine, Romero et al. in preparation).
                                                                                                                    (ii) The genus Flavivirus provides a particularly rich system in which to investigate the molecular determinants of vector infectivity, since the nearly 80 species of flaviviruses group into three lineages that differ in their mode of transmission: (a) mosquito-borne, (b) tick-borne and (c) no known vector (directly transmitted). Using site-directed mutagenesis, my lab is investigating molecular determinants of mode of transmission and vector infectivity and specificity in the flaviviruses (Romero et al. 2006, Maes et al. in preparation, Tumban et al. in preparation).
 

Representative Publications

• Vasilakis, N., E. J. Shell, E.B. Fokam, P.W. Mason, K.A. Hanley, D.M. Estes, and S.C.Weaver. 2007. Potential of ancestral sylvatic dengue-2 viruses to re-emerge.
  Virology 358(2):402-12.[PDF]

• T.A. Romero, E. Tumban, J. Jun, W.B. Lott, and K.A. Hanley.  2006. Secondary structure of dengue virus type 4 3’ untranslated region: Impact of deletion and substitution mutations. Journal of General Virology 87:3291–3296. [PDF]
   

• Hanley, K.A., L.B. Goddard, L.E. Gilmore, T.W. Scott, J. Speicher, B.R. Murphy, A. G. Pletnev. 2005.  Infectivity of West Nile/Dengue chimeric viruses for West Nile and Dengue mosquito vectors. Vector-Borne and Zoonotic Diseases 5: 1-10. [PDF]
   

• Hanley, K.A., L.R. Manlucu, G.G. Manipon, C.T. Hanson, S.S. Whitehead, B.R. Murphy, J.E. Blaney Jr. 2004. Introduction of mutations into the non-structural genes or 3’ untranslated region of an attenuated dengue virus type 4 vaccine candidate further decreases replication in rhesus monkeys while retaining protective immunity. Vaccine 22:3440-3448. [PDF]
   

• Burch, C.L., P.E. Turner, and K.A. Hanley.  2003. Patterns of epistasis in RNA viruses: a review of the evidence from vaccine design. Journal of Evolutionary Biology 16:1223-1235. [PDF]
   

• Hanley, K.A., L.R. Manlucu, L.E. Gilmore, J.E. Blaney Jr., C. T. Hanson, B.R. Murphy and S.S. Whitehead. 2003.  A trade-off in replication in mosquito versus mammalian systems conferred by a point mutation in the NS4B protein of dengue virus type 4. Virology 312: 222-232. [PDF]

Updated: February, 2008