A target for intervention in Plasmodium falciparum infections.

Abstract

We present a set of simple mathematical models to investigate interactions between malaria parasites and the human immune system and the differentiation of parasites from asexual, pathogenic into sexual, transmissible blood stages. Each model represents a different combination of empirically based hypotheses, and salient behaviors of each fit criteria developed from clinical data. In all models, however, higher gametocyte conversion rates result in lower peak asexual-form densities. Therefore, to the extent that asexual-form densities are associated with disease symptoms, interventions that stimulate gametocytogenesis should produce unexpected clinical benefits.In many infectious diseases the severity of clinical symptoms appears to vary directly with pathogen density. Though Plasmodium falciparum infections exhibit remarkably wide variation across individuals, populations and particular symptoms, in general terms worse prognoses are associated with higher asexual parasitemias. 1-12 Most antimalarial drugs aim to kill asexual blood-stage parasites precisely because pathogenesis is associated solely with merogony.No disease symptoms are associated with gametocytes, the sexual, transmissible forms that may develop from asexual blood-stage parasites, and it is widely accepted that the few host immune responses provoked by gametocytes act only against the life-cycle stages that may subsequently develop within a vector mosquito. 13-15 , but see 16 The factors that trigger and regulate the production of gametocytes remain largely mysterious. 17, 18 The once-common view that conversion is related to some element(s) of host immunity has faded considerably following the demonstration of gametocytogenesis in long-term culture; 19 emphasis has shifted toward genetic or more direct environmental mechanisms. 20-21 , but see 22 As with the relationship between asexual-form density and clinical severity, higher gametocyte densities are generally but loosely associated with greater infectivities to mosquitoes. 13,[23][24][25] At the human population level, Schuffner's 26 study of malaria in epidemic and endemic regions of Sumatra showed that in both regions P. falciparum gametocyte prevalence roughly tracks asexual-form prevalence, remaining high and relatively constant across age groups during an epidemic but decreasing with age at an endemic site. In Sri Lanka, an area of epidemic P. falciparum malaria, gametocyte prevalence decreases with age, while infectivity measures show no clear trends. 27 Githeko and others 28 supported Muirhead-Thomson's 29 conclusions that in endemic regions of Africa gametocyte prevalence decreases with age and older gametocyte carriers are typically less infectious; however, Githeko and others added the crucial observation that the ratio of circulating sexual-to-asexual-form densities increases with host age. In a P. falciparum endemic region of India, gametocyte densities are lower but conversion rates are higher among adults. 30Epidemiologic surveys invariably report much lower prevalence...

Gametocytemia and infectivity to mosquitoes of patients with uncomplicated Plasmodium falciparum malaria attacks treated with chloroquine or sulfadoxine plus pyrimethamine.

“…40 This time lag is in agreement with models proposed recently that predict that an optimizing pathogen should delay production of its transmission stages. 41,42 The higher gametocytemia before treatment in CQ-resistant infections in comparison with sensitive ones has already been observed in other studies in Senegal 29,30 and the Solomon Islands. 43 This might be explained by a higher gametocytogenesis as observed in vitro in CQ-resistant parasites; 28 furthermore, Hogh and others observed that patients harboring CQ-resistant parasites were 4.4 times more likely to produce gametocytes as those harboring sensitive ones.…”

Synchronous versus asynchronous oscillations for antigenically varyingPlasmodium falciparumwith host immune response

“…That is, there is a delay between changes in the Pf population and production of corresponding immune effectors. Delays have been used in disease models with an IR in [17], and for malaria in particular in [13,18,19]. However, we are not aware of any reported measurements of IR delay times for Pf.…”

Age-structured red blood cell susceptibility and the dynamics of malaria infections

“…We do not consider parasite synchronization, which is likely immune-mediated (27), but note that it would probably benefit the host of a P. vivax infection were reticulocyte susceptibility Ͻ48 h. We also do not consider the blood stages transmissible to mosquitoes; their production entails complex trade-offs between density, persistence, pathogenesis, and transmission (28,29), but these should not alter the qualitative conclusions given here. Here, any correlates of the peak infected RBC count would be maximized simply by maximizing R 0 and f 0 ; larger R 0 values also lead more quickly to catastrophic anemia, however, and correlates of the integrated infected RBC count would be maximized by species-specific balances between R 0 and f 0 .…”