Plasmodium falciparum malaria is one of mankind's main killers. Part of the parasite's life-cycle is spent in human blood, mainly as asexual stages. A fraction of the asexual parasites develops into gametocytes (gamete precursors) while sequestered in deep tissues. After re-entering the circulation, gametocytes can be picked up by a mosquito to continue the parasite's life-cycle. We present estimates of the conversion probability from asexual parasites to circulating gametocytes and of the gametocytes' sequestration and circulation times, obtained for the first time by fitting a dynamic model to individual patients' histories (daily records of 113 neurosyphilitic patients undergoing malariatherapy). The model assumes that the conversion probability can vary among the successive waves of asexual parasitaemia of a patient, and that gametocytes die at an age-dependent rate which increases under high asexual parasite densities. On average, 1 gametocyte per 156 asexual parasites (range 7.4-3700) is produced. The most remarkable findings are the large individual variation of conversion probabilities and circulation times, the average gametocyte circulation time of 6.4 days (range 1.3-22.2 days) which is more than twice the currently accepted value, and the large variation of conversion probabilities among successive waves of asexual parasitaemia without any particular time pattern. The latter finding could be explained by an association between conversion probability and variation of PfEMP1.

A new mathematical model of Plasmodium falciparum asexual parasitaemia is formulated and fitted to 35 malaria therapy cases making a spontaneous recovery after primary inoculation. Observed and simulated case-histories are compared with respect to 9 descriptive statistics. The simulated courses of parasitaemia are more realistic than any previously published. The model uses a discrete time-step of 2 days. Its realistic behaviour was achieved by the following combination of features (i) intra-clonal antigenic variation, (ii) large variations of the variants' baseline growth rate, depending on both variant and case, (iii) innate autoregulation of the asexual parasite density, variable among cases, (iv) acquired variant-specific immunity and (v) acquired variant-transcending immunity, variable among cases. Aspects of the model's internal behaviour, concerning variant dynamics, as well as the respective contributions of the three control mechanisms (iii) – (v), are displayed. Some implications for pathogenesis and control are discussed.

Algorithms for Spectral Analysis of Irregularly Sampled Time Series

T-cell prolymphocytic leukemia (T-PLL) is a poor-prognostic neoplasm. Differentiation stage and immune-effector functions of the underlying tumor cell are insufficiently characterized. Constitutive activation of the T-cell leukemia 1A (TCL1A) oncogene distinguishes the (pre)leukemic cell from regular postthymic T cells. We assessed activation-response patterns of the T-PLL lymphocyte and interrogated the modulatory impact by TCL1A. Immunophenotypic and gene expression profiles revealed a unique spectrum of memory-type differentiation of T-PLL with predominant central-memory stages and frequent noncanonical patterns. Virtually all T-PLL expressed a T-cell receptor (TCR) and/or CD28-coreceptor without overrepresentation of specific TCR clonotypes. The highly activated leukemic cells also revealed losses of negative-regulatory TCR coreceptors (eg, CTLA4). TCR stimulation of T-PLL cells evoked higher-than-normal cell-cycle transition and profiles of cytokine release that resembled those of normal memory T cells. More activated phenotypes and higher TCL1A correlated with inferior clinical outcomes. TCL1A was linked to the marked resistance of T-PLL to activation- and FAS-induced cell death. Enforced TCL1A enhanced phospho-activation of TCR kinases, second-messenger generation, and JAK/STAT or NFAT transcriptional responses. This reduced the input thresholds for IL-2 secretion in a sensitizer-like fashion. Mice of TCL1A-initiated protracted T-PLL development resembled such features. When equipped with epitope-defined TCRs or chimeric antigen receptors, these Lckpr-hTCL1Atg T cells gained a leukemogenic growth advantage in scenarios of receptor stimulation. Overall, we propose a model of T-PLL pathogenesis in which TCL1A enhances TCR signals and drives the accumulation of death-resistant memory-type cells that use amplified low-level stimulatory input, and whose loss of negative coregulators additionally maintains their activated state. Treatment rationales are provided by combined interception in TCR and survival signaling.