Part 1 The importance of blood-sucking insects. Part 2 The evolution of the blood-sucking habit: prolonged close association with vertebrates morphological pre-adaptation for piercing. Part 3 Feeding preferences of blood-sucking insects: host choice host choice and species complexes. Part 4 Location of the host: the behavioural framework of host location appetitive searching activation and orientation attraction movement between hosts. Part 5 Ingestion of the blood meal: vertebrate haemostasis insect anti-haemostatic factors probing stimulants phagostimulants mouthparts blood intake. Part 6 Managing the blood meal: midgut anatomy the blood meal gonotrophic concordance nutrition host hormones in the blood meal partitioning of resources from the blood meal autogeny. Part 7 Host - insect interactions: insect distribution on the surface of the host morphological specializations for life on the host host immune responses to insect salivary secretions behavioural defences of the host density dependent effects on feeding success. Part 8 Transmission of parasites by blood-sucking insects: transmission routes specificity in vector-parasite relationships origin of vector parasite relationships.

Biology of Blood-Sucking Insects

The circadian rhythm of body temperature.

Plasmodium vivax is a major cause of febrile illness in endemic areas of Asia, Central and South America, and the horn of Africa. Plasmodium vivax infections are characterized by relapses of malaria arising from persistent liver stages of the parasite (hypnozoites) which can be prevented only by 8-aminoquinoline anti-malarials. Tropical P. vivax relapses at three week intervals if rapidly eliminated anti-malarials are given for treatment, whereas in temperate regions and parts of the sub-tropics P. vivax infections are characterized either by a long incubation or a long-latency period between illness and relapse - in both cases approximating 8-10 months. The epidemiology of the different relapse phenotypes has not been defined adequately despite obvious relevance to malaria control and elimination. The number of sporozoites inoculated by the anopheline mosquito is an important determinant of both the timing and the number of relapses. The intervals between relapses display a remarkable periodicity which has not been explained. Evidence is presented that the proportion of patients who have successive relapses is relatively constant and that the factor which activates hypnozoites and leads to regular interval relapse in vivax malaria is the systemic febrile illness itself. It is proposed that in endemic areas a large proportion of the population harbours latent hypnozoites which can be activated by a systemic illness such as vivax or falciparum malaria. This explains the high rates of vivax following falciparum malaria, the high proportion of heterologous genotypes in relapses, the higher rates of relapse in people living in endemic areas compared with artificial infection studies, and, by facilitating recombination between different genotypes, contributes to P. vivax genetic diversity particularly in low transmission settings. Long-latency P. vivax phenotypes may be more widespread and more prevalent than currently thought. These observations have important implications for the assessment of radical treatment efficacy and for malaria control and elimination.

/pdf/determinants-of-relapse-periodicity-in-plasmodium-vivax-1yffn6am3n.pdf

Determinants of relapse periodicity in Plasmodium vivax malaria.

Malaria is a mosquito-borne disease that is transmitted by inoculation of the Plasmodium parasite sporozoite stage Sporozoites invade hepatocytes, transform into liver stages, and subsequent liver-stage development ultimately results in release of pathogenic merozoites Liver stages of the parasite are a prime target for malaria vaccines because they can be completely eliminated by sterilizing immune responses, thereby preventing malarial infection Using expression profiling, we previously identified genes that are only expressed in the pre-erythrocytic stages of the parasite Here, we show by reverse genetics that one identified gene, UIS3 (upregulated in infective sporozoites gene 3), is essential for early liver-stage development uis3-deficient sporozoites infect hepatocytes but are unable to establish blood-stage infections in vivo, and thus do not lead to disease Immunization with uis3-deficient sporozoites confers complete protection against infectious sporozoite challenge in a rodent malaria model This protection is sustained and stage specific Our findings demonstrate that a safe and effective, genetically attenuated whole-organism malaria vaccine is possible

Genetically modified Plasmodium parasites as a protective experimental malaria vaccine

Antifolate antimalarial drugs interfere with folate metabolism, a pathway essential to malaria parasite survival. This class of drugs includes effective causal prophylactic and therapeutic agents, some of which act synergistically when used in combination. Unfortunately, the antifolates have proven susceptible to resistance in the malaria parasite. Resistance is caused by point mutations in dihydrofolate reductase and dihydropteroate synthase, the two key enzymes in the folate biosynthetic pathway that are targeted by the antifolates. Resistance to these drugs arises relatively rapidly in response to drug pressure and is now common worldwide. Nevertheless, antifolate drugs remain first-line agents in several sub-Saharan African countries where chloroquine resistance is widespread, at least partially because they remain the only affordable, effective alternative. New antifolate combinations that are more effective against resistant parasites are being developed and in one case, recently introduced into use. Combining these antifolates with drugs that act on different targets in the parasite should greatly enhance their effectiveness as well as deter the development of resistance. Molecular epidemiological techniques for monitoring parasite drug resistance may contribute to development of strategies for prolonging the useful therapeutic life of this important class of drugs.

Mechanisms of Resistance of Malaria Parasites to Antifolates

Experimental maintenance of Dirofilaria repens and D. immitis in dogs.

1. 1. The 24-, 48- and 72-hour cycles of asexual malaria parasites in the blood are remarkable because (a) these periods are simple multiples of 24 hours, (b) all parasites behave synchronously and come to schizogony at the same time and, (c) schizogony occurs at an hour constant for each species (mid-day for plasmodia of man and monkeys, early morning or late evening for some plasmodia of birds). 2. 2. We speculated that these cycles might be connected with transmission by mosquitoes which bite only at night; but this explanation encountered the difficulty that the asexual parasites (which show the cycle) do not develop in mosquitoes, while orthodox views considered the gametocytes (which do develop in mosquitoes) to show no cycle but to remain unchanged in the blood for many days. We therefore re-investigated the gametocytes. 3. 3. Our studies on Plasmodium knowlesi, P. cynomolgi and P. cathemerium have demonstrated that there is in fact a cycle in the infectivity of gametocytes for mosquitoes and in the readiness of the male gametocyte to exflagellate. Both these come to a peak about midnight and fall to low levels during the day. A corresponding cycle can be demonstrated in the morphology of the gametocytes. 4. 4. Accordingly, we consider that the conception of long-lived gametocytes is incorrect. Actually gametocytes take a few hours longer than their asexual cycle to develop to the stage of infectivity for mosquitoes, they remain mature for only a short period (5–12 hours) and then they quickly degenerate and disappear. The illusion of unchanged gametocytes persisting in the blood for long periods is due to the constant replacement of short-lived individuals by a succession of new gametocytes derived from each schizogony. This statement probably applies to all plasmodia which show a synchronous asexual cycle, with the possible exception of P. falciparum which is unique in that the gametocytes take 9–12 days to develop and which requires special investigation. 5. 5. We conclude that the biological function of the synchronous cycle of asexual malaria parasites is to ensure that the short-lived appearance of mature gametocytes in the blood should coincide with the limited time at which vector mosquitoes suck blood (i.e. at night) and in this way to facilitate transmission; in short, it serves to make the gametocytes match the mosquitoes. 6. 6. The synchronization and orientation of the asexual plasmodial cycle are entrained by the temperature cycle of the host. If the temperature cycle of the host is inverted (e.g. by artificially lowering it to 35° during the daytime), the plasmodial cycle also becomes inverted after a lag of 2–4 cycles, and schizogony occurs at midnight instead of mid-day. This has been demonstrated with P. knowlesi and P. cynomolgi in monkeys and has been confirmed with P. cathemerium in duck embryos. 7. 7. When the temperature cycle of the host is allowed to return to normal, the malaria cycle gradually reverts to normal also, with a lag of 8 or more cycles. During this reversion the cycle of P. cynomolgi may be lengthened to 49 hours or shortened to 47 hours (instead of the normal 48 hours). Apparently malaria cycles which are slightly longer or shorter than a multiple of 24 hours represent a transitional phase of readjustment to the abnormal cycle of the host which has itself been altered by the infection.

24- and 48-hour cycles of malaria parasites in the blood; their purpose, production and control

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1476-5381.1950.tb01010.x

The mode of action of hetrazan on filarial worms.

Two autopsies are described of cases of rhodesiense sleeping-sickness, in which no appreciable treatment had been received. There were extensive trypanosomal effusions in the pleural, peritoneal and pericardial cavities, and marked inflammation of the myocardium, epicardium and endocardium. These visceral lesions were closely similar to those described by Peruzzi in the trypanosomiasis of monkeys. The cerebrospinal fluids of these cases contained numerous trypanosomes but the cell-count and protein content were not much raised; corresponding to this pathological pattern in the fluid, the histological lesions in the central nervous system were very slight, being limited to a histiocytic infiltration of the cerebral membranes. From these cases and from experiments in vitro, it is concluded that it is not possible to have a true invasion of the cerebrospinal fluid by trypanosomes until the protein content is considerably increased. In the absence of treatment, the visceral lesions of rhodesiense sleeping-sickness are probably more often fatal than the lesions of the nervous system.

These two cases also suffered from widespread infection with tuberculosis.

Two autopsies on rhodesiense sleeping sickness; Visceral lesions and significance of changes in cerebrospinal fluid

Summary (1) A study of the periodicity of microfilarise has been made in monkeys naturally infected by a worm which probably belongs to the genus Dirofilaria. The microfilariae have a nocturnal periodicity similar to that of Wuchereria bancrofti. Subsidiary studies have been made on other similar filarial infections of monkeys and on Dirofilaria repens of dogs. (2) By means of an empirical technique, the number of microfilariae counted in a histological section can be used to calculate the total number of microfilariae present in an organ or tissue. (3) Complete postmortem examinations have been made on five monkeys and four dogs, half of them killed at midday and half at midnight, respectively. Shortly before and after death (if it occurs in the day) great numbers of microfilariae are liberated from the lungs, so that the blood of the left ventricle contains many more than were present in the circulating blood before the animal was killed. This agonal event accounts for Manson's erroneous suggestion that the microfilariae retired during the day to the heart and great vessels (as well as to the lungs). (4) At postmortem examination, the organs of the body (apart from the lungs) contain only small numbers of microfilariae either by day or night. Over 80 per cent. of the total number of microfilariae in the body are usually contained in the lungs and in the blood. There are proportionately more microfilariae in the lungs of animals killed by day than in those killed by night, and conversely for the microfilariae in the blood. (5) Pairs of specimens were taken for biopsy by day and by night respectively from most of the organs of the body. The microfilariae present in the liver, spleen, marrow, lymph glands, skin and muscle were relatively few, and often there were more present by night than by day. The lungs contained very many microfilariae at all times. In seven out of eight experiments there were more microfilariae in the lungs by day than there were by night and the accumulation of microfilariae in the lungs during the day was amply large enough to account for the microfilariae which had disappeared from the blood during this period. (6) No evidence was obtained that the accumulation of microfilariae in the lung causes significant pathological lesions. (7) Direct observations were made on the behaviour of living, microfilariae in the intact circulation of infected cotton-rats and dogs. The microfilariae seemed to pass through the capillaries rapidly and smoothly; and accumulation in the small vessels was not observed except as a terminal event before death of the host.

Frank Hawking

Papers

Experimental maintenance of Dirofilaria repens and D. immitis in dogs.

24- and 48-hour cycles of malaria parasites in the blood; their purpose, production and control

The mode of action of hetrazan on filarial worms.

Two autopsies on rhodesiense sleeping sickness; Visceral lesions and significance of changes in cerebrospinal fluid

The periodicity of microfilariae. I. The distribution of microfilariae in the body.