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Human settlements and scrub typhus: where do humans come into contact with infected chigger mite larvae? - NU/LSHTM project

Title of PhD project / theme

Human settlements and scrub typhus: where do humans come into contact with infected chigger mite larvae?

Supervisory team

Wolf-Peter Schmidt, LSHTM/DCD, wolf-peter.schmidt@lshtm.ac.uk (Lead)

Yamanashi Hirotomo, Nagasaki University, yhirotomo@yahoo.co.jp

Yoshinao Kubo, Nagasaki University, yoshinao@nagasaki-u.ac.jp

Neal Alexander, LSHTM, TEG, neal.alexander@lshtm.ac.uk

Mary Cameron, LSHTM, DCD, mary.cameron@lshtm.ac.uk

John AJ Prakash, Christian Medical College Vellore (CMC), prakjaj@cmcvellore.ac.in

Brief description of project / theme

Background: Scrub typhus is a potentially life-threatening febrile illness caused by bacterial species belonging to the genus Orientia (family Rickettsiaceae).1 The infection is transmitted by the larvae (chiggers) of trombiculid mites.2 Despite being a common cause of fever over much of tropical and subtropical Asia, little is known about where infestation of humans with chiggers occurs. Traditionally, infestation is thought to occur during agricultural work in fields, in villages or on plantations.3 However, people living in agricultural villages without doing agricultural work are also at risk.4 Chiggers are known to live in vegetation such as grass and bushes, waiting to transfer to vertebrate hosts, especially rodents.5 Mites favour humid environments in the wet season, and do not tolerate well dry conditions.3 In endemic villages, infestation could conceivably occur in the fields away from the village where rodent density may be low but where vegetation is abundant, or at the edge of the village where vegetation and rodents may also be present in sufficient numbers to allow mites to complete their lifecycle. Infestation could also occur within a village for example around man-made water sources and drains where rodents and shrubs/grass may be able to thrive.

Aims and objectives: This PhD project seeks to better understand in which environments infestation of humans with Orientia tsutsugamushi-infected chiggers occurs. This will be done by seeking eco-epidemiological associations between human antibody levels and inferred exposure to vectors, based on the abundance of the rodents and vectors, in different types of location such as: fields away from the village, village edge and within the village. Specific objectives can be determined by the student in collaboration with the supervisors but may involve estimating various measures of rodent and vector abundance, the prevalence of O. tsutsugamushi infection in chiggers by species, and associations between the rodent and vector parameters and data on human scrub typhus infection, accounting for human behaviour data.

Methods:   

Setting: The proposed PhD will be done in the context of a large population based cohort study on rickettsial infections in the South Indian district of Vellore, conducted by LSHTM and the Christian Medical College, Vellore and funded by UK MRC (budget GBP 790,000). The budget fully covers PhD research costs including field work, lab materials and consumables.

During the baseline survey (February to July 2020) we have collected blood samples for serology from 5400 geo-referenced individuals living in 34 study villages. These individuals will be revisited annually to obtain data on sero-prevalence and sero-incidence. The individuals are part of a larger cohort study of 30,000 people followed up for clinical scrub typhus infection. The student will be given access to these data on human scrub typhus infection. Rodents will be collected by the research team from April 2021 for 12 months in three types of location: fields away from the village, village edge and within the village. The student may contribute to field work, for example by collecting data on human behaviour, or by conducting additional rodent catches.

Laboratory work: The extent of laboratory work will depend on the student’s preferences and skills. Identification of chiggers to species level, and estimating Orientia infection in chiggers should be the focus of the work. This could involve quantitative or nested PCR. Sequencing to determine genotypes of Orientia is a further option. The student is expected to identify suitable laboratory and chigger identification methods. 

Analysis: The student is expected to identify measures of rodent and vector abundance. Further the student will identify suitable methods of exploring associations between Orientia prevalence in chiggers and human scrub typhus data (e.g. sero-prevalence, sero-incidence, incidence of clinical infection). The student may also include human behaviour if collection of such data s chosen as part of this work.

Importance of this work: Despite being a dominant cause of complicated febrile illness in South and East Asia, the most populous region in the world, the epidemiology of scrub typhus remains poorly understood. This will be the first study to link detailed human serological data to exposure risk to vectors, thus advancing our knowledge on the eco-epidemiology of O. tsutsugamushi transmission in a highly endemic setting.

Timeline:

October 2021 – January 2022: Orientation and finalising the PhD research plan

February 2022 – September 2022: Field work at Vellore study site (mainly lab based, contribution to rodent collection is optional)

October 2022: Upgrading

November 2022 – September 2023: Data analysis (chigger speciation, statistical analysis)

 From October 2023: write up

References:

1.         Tamura A, Ohashi N, Urakami H, Miyamura S. Classification of Rickettsia tsutsugamushi in a new genus, Orientia gen. nov., as Orientia tsutsugamushi comb. nov. Int J Syst Bacteriol 1995; 45(3): 589-91.

2.         Paris DH, Shelite TR, Day NP, Walker DH. Unresolved problems related to scrub typhus: a seriously neglected life-threatening disease. Am J Trop Med Hyg 2013; 89(2): 301-7.

3.         Elliott I, Pearson I, Dahal P, Thomas NV, Roberts T, Newton PN. Scrub typhus ecology: a systematic review of Orientia in vectors and hosts. Parasit Vectors 2019; 12(1): 513.

4. Devamani CS, Schmidt WP, Ariyoshi K, Anitha A, Kalaimani S, Prakash JAJ. Risk Factors for Scrub Typhus, Murine Typhus, and Spotted Fever Seropositivity in Urban Areas, Rural Plains, and Peri-Forest Hill Villages in South India: A Cross-Sectional Study. Am J Trop Med Hyg 2020.

The role of LSHTM and NU in this collaborative project

NU is already collaborating with LSHTM on the MRC cohort study on rickettsial infection by supervising a PhD student working on human scrub typhus incidence (Professor Koya Ariyoshi).

NU has established expertise in the epidemiology and molecular diagnostics of rickettsial infections, including scrub typhus, and has a track record of publications in this field. LSHTM is the lead institution for the MRC cohort study on rickettsial infections and has expertise in the sero-epidemiology of rickettsial infections (3 publications) and in conducting large cohort studies. LSHTM also has expertise in vector sampling and identification of mites and ticks.

The two institutions ideally complement each others’ expertise, with NU leading on the molecular laboratory methods and LSHTM on epidemiological methods and vector sampling/identification.

Particular prior educational requirements for a student undertaking this project

This PhD is suitable for students with a background in microbiology, molecular biology, ecology or medicine/veterinary medicine. Proven skills in molecular methods in particular qPCR/nPCR are essential. Proven interest or publications in Rickettsial infection is desirable.

Skills we expect a student to develop/acquire whilst pursuing this project

The student will be expected to further his/her skills in molecular methods, in particular pathogen detection in disease vectors. The student will develop skills in genome sequencing and chigger species identification. The students will have the opportunity to develop skills in field work, collecting household level data (essential), vector sampling methods (optional) and data analysis (essential).