# Genetic determinants of pre-erythrocytic parasite fitness

> **NIH NIH P01** · UNIVERSITY OF NOTRE DAME · 2024 · $492,953

## Abstract

PROJECT SUMMARY
We have pioneered a human-liver chimeric mouse model that supports Plasmodium falciparum liver stage
development and transition to blood stage infection and used this model in the first P01 to successfully
conduct more genetic crosses than have ever been achieved in the past and recovered hundreds of
recombinant progeny. This has been pivotal to map genetic traits regulating important parasite phenotypes
such as drug resistance. The biology of drug resistance is overwhelmingly studied in asexual blood stages
because it is at this stage that drug resistance is of clinical relevance. However, for drug resistant parasites
to spread through a human population, parasites must develop in a mosquito vector for onward transmission
to human hosts and spread in the human population. Upon human infection, parasites must then be able to
complete liver stage development and transition back to the blood stage infection to cause clinical disease
and for onward transmission. This is extremely relevant to the evolution and spread of drug resistance since
recombination could speed the acquisition and spread of resistance-associated genes in the field by
introgression of genes that (i) enhance transmission fitness and (ii) pre-erythrocytic infection fitness, into
drug-resistant parasite populations. This P01 Research Project will use genetic crosses to understand genetic
factors involved in parasite fitness across the mosquito stages and pre-erythrocytic stages of the life cycle.
We will determine if and how, after mating of two distinct parasite strains, particularly drug resistant and drug
sensitive strains, recombinant progeny utilize fitness advantages to outcompete parent strains. Using
distinctly fluorescent parental lines, we have already shown that both recombinant and parent oocysts are
readily formed in the mosquito midgut. We will thus determine if superior recombinant parasite fitness during
sporogony and/or sporozoite salivary gland colonization increases the success of human host infection and
identify the genetic loci that control these fitness traits. We have also shown that recombinant parasite
progeny can have enhanced fitness in human liver cell infection when compared to parent strains. We will
thus identify the genetic factors that determine sporozoite infection for human hepatocytes using parents and
recombinant parasites which show differences in levels of infectivity for human hepatocytes and differences
in successful establishment of the intra-hepatocytic replication niche. Finally, we will determine genetic factors
that enhance liver stage growth and duration of maturation into exo-erythrocytic merozoites and thereby give
a head start in initiating blood stage infection. This work will unravel factors controlling parasite fitness during
the mosquito stages and pre-erythrocytic stages of development and will show how these may enhance the
spread of drug resistant parasites.

## Key facts

- **NIH application ID:** 10863151
- **Project number:** 2P01AI127338-06A1
- **Recipient organization:** UNIVERSITY OF NOTRE DAME
- **Principal Investigator:** Stefan HI Kappe
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $492,953
- **Award type:** 2
- **Project period:** 2017-08-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10863151

## Citation

> US National Institutes of Health, RePORTER application 10863151, Genetic determinants of pre-erythrocytic parasite fitness (2P01AI127338-06A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10863151. Licensed CC0.

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