Biology subjects

Mordmueller, B.

Publications and source records attributed to Mordmueller, B..

5 recordsLinked to original sources

bioRxiv2026

Deep behavioral phenotyping of pathogen infected mosquitoes reveals species-specific behavior changes enhancing transmission

Mosquito-borne pathogens are often proposed to alter mosquito behavior to enhance transmission, yet the prevalence, magnitude, and consequences of such effects remain unclear. Using custom high- throughput behavioral assays and deep-learning analysis, we quantified the blood-feeding behavior of more than 5,000 mosquitoes, and long-term activity patterns of more than 1,000 mosquitoes across six clinically relevant mosquito-pathogen combinations. Infection effects were highly species-specific. Anopheles stephensi infected with an African Plasmodium falciparum strain showed elevated flight activity throughout infection, an increased tendency to blood-feed upon host contact, and prolonged feeding times. In contrast, infection with an Asian P. falciparum strain or P. vivax had little impact on An. stephensi behavior. We detected no behavioral changes associated with P. falciparum infection in Anopheles gambiae s.s. or Anopheles coluzzii. Interestingly, dengue virus infection in Aedes aegypti increased landing, probing, and engorgement rates. Together, these results demonstrate that infection-induced behavioral change is not a general phenomenon among mosquito-borne pathogens, yet differs markedly per mosquito and pathogen species. A transmission model parameterized with our data showed that even modest behavioral shifts can substantially increase transmission, underscoring the potential epidemiological importance of subtle phenotypic shifts.

animal behavior and cognition↗

bioRxiv2026

Quantifying sporozoite inoculum dynamics with the SpitGrid reveals temporal decay and behavioral determinants of Plasmodium transmission

The number of Plasmodium sporozoites expelled by an infected mosquito during a bite, the inoculum size, is a critical but rarely measured factor in transmission. Its temporal dynamics, individual variation, and behavioral underpinnings remain poorly understood. To address this, we developed the SpitGrid, a modular platform that supports natural probing and feeding on artificial substrates, while enabling behavioral characterization combined with non-lethal, sensitive measurement of inoculum size for individual mosquitoes in high-throughput. Using the SpitGrid, we determined inoculum size of Plasmodium falciparum-infected Anopheles stephensi mosquitoes over time and identified a robust temporal structure. Inoculum size peaked shortly after the extrinsic incubation period, and declined approximately log-linearly post peak. Salivary gland parasite load decreased only moderately and was positively associated with inoculum size during the early phase of sporozoite expelling, yet explained only part of the variation observed in inoculum size. Fine-grained behavioral classification confirmed that probing alone can deliver substantial inocula, and revealed that probing more often increased inoculum size while the duration of probing, or if this led to feeding, had little effect. Application of the SpitGrid to Plasmodium vivax-infected mosquitoes similarly showed a temporally structured expelling profile, with generally smaller inocula and a higher proportion of non-expelling mosquitoes. Our observations reveal that Plasmodium infectivity in mosquitoes is a highly dynamics process, challenging the assumption that per-bite transmission potential remains constant over time. We establish the SpitGrid as a flexible tool to gain a nuanced understanding of the determinants of transmission, refine epidemiological models, and evaluate the efficacy of vector- based interventions under biologically relevant conditions. HighlightsWe develop the SpitGrid, a flexible, accessible, low-cost and animal free platform to measure sporozoite expelling We identify a peak in P. falciparum and P. vivax sporozoite expelling by infected Anopheles stephensi mosquitoes early after completion of the extrinsic incubation period, followed by a gradual decline We confirm a correlation between salivary gland load and inoculum size that weakens over time, indicating that a smaller fraction of the remaining salivary gland load is being expelled by older mosquitoes We confirm that mosquito probing alone can deliver substantial sporozoite inoculum independently of a successful bloodmeal By dissecting the behavioral parameters that determine inoculum size, we observe that the initiation of probing is a major determinant of inoculum size with relatively minor roles for probing time and whether biting results in engorgement Compared to P. falciparum, we observe comparatively smaller inocula, in P. vivax-infected mosquitoes a higher rate of non-expellers and similar albeit more moderate temporal structure with an earlier onset of expelling, illustrating cross-species utility of the SpitGrid

microbiology↗

bioRxiv2023

Molecular and functional properties of human Plasmodium falciparum CSP C-terminus antibodies

Human monoclonal antibodies (mAbs) against the central repeat and junction domain of Plasmodium falciparum circumsporozoite protein (PfCSP) have been studied extensively to guide malaria vaccine design compared to antibodies against the PfCSP C terminus. Here, we describe the molecular characteristics and protective potential of a panel of 73 germline and mutated human mAbs against the highly immunogenic PfCSP C-terminal domain. Two mAbs recognized linear epitopes in the C-terminal linker with sequence similarity to repeat and junction motifs, whereas all others targeted conformational epitopes in the -thrombospondin repeat (-TSR) domain. Specificity for the polymorphic Th2R/Th3R but not the conserved RII+ region in the -TSR was associated with IGHV3-21/IGVL3-21 or IGLV3-1 gene usage. Although the C terminus specific mAbs showed signs of more efficient affinity maturation and class-switching compared to anti-repeat mAbs, parasite inhibitory activity was limited to a single C-linker reactive mAb with cross-reactivity to the central repeat and junction. The data provide novel insights in the human anti-C-linker and anti--TSR antibody response that support exclusion of the PfCSP C terminus from malaria vaccine designs.

immunology↗

bioRxiv2021

Clonal evolution and specificity of the human T follicular helper cell response to Plasmodium falciparum circumsporozoite protein

T follicular helper (TFH) cells play a crucial role in the development of long-lived, quality-improved B cell responses after infection and vaccination. However, little is known about their clonal evolution. Here we assessed the cell phenotype, clonal dynamics, and TCR specificity of human circulating TFH (cTFH) cells at monoclonal level during successive malaria immunizations with radiation-attenuated Plasmodium falciparum (Pf) sporozoites. Repeated parasite exposures induced a dynamic, polyclonal cTFH response with high frequency of cells specific to the Pf circumsporozoite protein (PfCSP), the main surface protein of sporozoites and a validated vaccine target. Repeated immunizations were required to induce detectable PfCSP-reactive cTFH cell responses to a small number of epitopes. HLA-restrictions and differences in TCR generation probability explain the high targeting frequency of the polymorphic Th2R/T* region over the conserved T1 epitope. The vast majority of anti-Th2R/T* TCRs failed to tolerate natural polymorphisms in their target peptide sequence suggesting that parasite diversity limits natural boosting of the cTFH cell response in endemic areas and protection from non-vaccine strains. Among convergent anti-Th2R/T* TCRs with high sequence similarity, subtle differences in CDR3 composition discriminated cross-reactive from non-cross-reactive cTFH cells. Thus, our study provides deep molecular and cellular insights into the kinetics, fine specificity and HLA-restrictions of the anti-cTFH cell response that are of direct relevance for the design of PfCSP-based malaria vaccines by guiding the selection of PfCSP peptides that induce optimal B cell help.

immunology↗

bioRxiv2020

Mapping of safe and early chemo-attenuated live Plasmodium falciparum immunization identifies immune signature of vaccine efficacy

Potent protection against malaria can be induced by attenuated live-immunization with Plasmodium falciparum (Pf) sporozoites (SPZ). However, a better understanding of the critical processes involved in the establishment of protective immunity is needed. We explored the safety and vaccine efficacy of early chemo-attenuation of PfSPZ under atovaquone-proguanil (AP). AP caused early arrest of P. berghei liver stages. Despite the absence of replication, robust protection in mice correlated with parasite-specific effector-memory CD8+ T-cell responses. In a phase I clinical trial a single dose of AP prevented Pf infections in the liver of adult, human subjects who received three doses of 5.12x104 or 1.5x105 PfSPZ by direct venous inoculation combined with oral AP. However, only 2 of 8 (25%) and 2 of 10 (20%), respectively, were protected against controlled human malaria infection (CHMI) 10 weeks after the last vaccine dose, despite levels of IgG antibodies to the Pf circumsporozoite protein (PfCSP) comparable to those achieved in fully protected volunteers after immunization with 5.12x104 PfSPZ with chloroquine chemoprophylaxis active only against subsequent blood stages. We identify lower IgG recognition of the secreted liver stage-specific antigens LISP2 and LSA1 and the multi-stage antigen MSP5 as immune signatures of inferior vaccine efficacy compared to PfSPZ with chloroquine chemoprophylaxis. In conclusion, we show that immune signatures of liver stage antigens, but neither an established rodent malaria model nor concentrations of antibodies against the major surface protein of sporozoites, permit prediction of vaccine efficacy. Thus, this study provides a clear rationale for the development of live sporozoite vaccination protocols that boost exposure to Pf liver stage antigens. Significance StatementOur research demonstrates that attenuation of liver infection of high doses of Plasmodium falciparum sporozoites by concomitant single-dose administration of atovaquone-proguanil is safe in humans. However, vaccine efficacy was modest when compared to an identical protocol using chloroquine that acts only on the subsequent blood infection. Immune signatures of secreted P. falciparum liver stage antigens, but neither an established rodent malaria model nor concentrations of sporozoite antibodies, permit prediction of vaccine efficacy.

immunology↗