Nomadic or sessile: can Kupffer cells function as portals for malaria sporozoites to the liver?

Frevert, Ute; Usynin, I. F.; Baer, Kerstin; Klotz, Christian

doi:10.1111/j.1462-5822.2006.00777.x

Cited by 48 publications

(47 citation statements)

References 97 publications

(146 reference statements)

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“…This study showed that anti-CD20 treatment leads to antibody-dependent phagocytosis of B cells by Kupffer cells in the liver (40). Kupffer cells usually act as silent portals of liver entry for sporozoites (41,42) but can reduce liver infection when nonspecifically activated (43). It is possible that systemic depletion of B cells by anti-CD20 treatment could activate Kupffer cells and nonspecifically reduce the parasite liver burden.…”

Section: Discussionmentioning

confidence: 85%

Purification of Plasmodium Sporozoites Enhances Parasite-Specific CD8 ⁺ T Cell Responses

2016

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cMalaria infection caused by Plasmodium parasites continues to cause enormous morbidity and mortality in areas where it is endemic, and there is no licensed vaccine capable of inducing sterile protection. Hyperimmunization with attenuated whole sporozoites can induce sterile protective immune responses targeting preerythrocytic antigens. Most animal models of hyperimmunization rely on sporozoites dissected from mosquito salivary glands and injected without further purification. In BALB/c mice, repeated small doses of P. yoelii sporozoites progressively expand the population of sporozoite-specific CD8 ؉ T cells. In this study, large secondary doses of unpurified sporozoites unexpectedly led to contraction of sporozoite-specific CD8 ؉ T cell responses in sporozoite-primed mice. While sporozoite-primed CD8 ؉ T cells alternatively can be expanded by secondary exposure to Listeria monocytogenes expressing recombinant Plasmodium antigens, such expansion was potently inhibited by coinjection of large doses of unpurified sporozoites and by uninfected salivary glands alone. Purification of sporozoites away from mosquito salivary gland debris by density gradient centrifugation eliminated salivary gland-associated inhibition. Thus, the inhibitory effect appears to be due to exposure to uninfected mosquito salivary glands rather than sporozoites. To further assess the effect of salivary gland exposure on later sporozoite vaccinations, mice were immunized with uninfected salivary glands from a single mosquito. Compared to naive mice, salivary gland presensitization reduced subsequent liver burdens by 71%. These data show that a component(s) in mosquito salivary glands reduces liver infection, thereby limiting antigen dose and contributing to lower-magnitude T cell responses. These findings suggest that sporozoite immunogenicity studies be performed using purified sporozoites whenever feasible.

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Section: Discussionmentioning

confidence: 85%

Purification of Plasmodium Sporozoites Enhances Parasite-Specific CD8 ⁺ T Cell Responses

2016

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“…In the liver, they cross the vascular endothelium by passage through resident Kupffer cells in order to reach the space of Disse (1,6). This allows them free access to hepatocytes (11).…”

mentioning

confidence: 99%

Plasmodium yoelii Sporozoites with Simultaneous Deletion of P52 and P36 Are Completely Attenuated and Confer Sterile Immunity against Infection

et al. 2007

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Malaria infection starts when sporozoites are transmitted to the mammalian host during a mosquito bite. Sporozoites enter the blood circulation, reach the liver, and infect hepatocytes. The formation of a parasitophorous vacuole (PV) establishes their intracellular niche. Recently, two members of the 6-Cys domain protein family, P52 and P36, were each shown to play an important albeit nonessential role in Plasmodium berghei sporozoite infectivity for the rodent host. Here, we generated p52/p36-deficient Plasmodium yoelii parasites by the simultaneous deletion of both genes using a single genetic manipulation. p52/p36-deficient parasites exhibited normal progression through the life cycle during blood-stage infection, transmission to mosquitoes, mosquito-stage development, and sporozoite infection of the salivary glands. p52/p36-deficient sporozoites also showed normal motility and cell traversal activity. However, immunofluorescence analysis and electron microscopic observations revealed that p52/p36-deficient parasites did not form a PV within hepatocytes in vitro and in vivo. The p52/p36-deficient parasites localized as free entities in the host cell cytoplasm or the host cell nucleoplasm and did not develop as liver stages. Consequently, they did not cause blood-stage infections even at high sporozoite inoculation doses. Mice immunized with p52/p36-deficient sporozoites were completely protected against infectious sporozoite challenge. Our results demonstrate for the first time the generation of two-locus gene deletion-attenuated parasites that infect the liver but do not progress to blood-stage infection. The study will critically guide the design of Plasmodium falciparum live attenuated malaria vaccines.

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“…CSP and TRAP are also crucial for sporozoite motility and infection of host cells (71). Sporozoites glide along the endothelium, then penetrate and traverse Kupffer cells to gain access to hepatocytes (72). Cell traversal seems to depend on at least two sporozoite secretory proteins, one of which contains a perforin-like membrane insertion domain that might allow the sporozoite to breach the cell membrane (73,74).…”

Section: Pathogenesis Immunity and Vaccinesmentioning

confidence: 99%

Malaria: progress, perils, and prospects for eradication

Greenwood¹,

Fidock²,

Kyle³

et al. 2008

J. Clin. Invest.

577

473

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There are still approximately 500 million cases of malaria and 1 million deaths from malaria each year. Yet recently, malaria incidence has been dramatically reduced in some parts of Africa by increasing deployment of antimosquito measures and new artemisinin-containing treatments, prompting renewed calls for global eradication. However, treatment and mosquito control currently depend on too few compounds and thus are vulnerable to the emergence of compound-resistant parasites and mosquitoes. As discussed in this Review, new drugs, vaccines, and insecticides, as well as improved surveillance methods, are research priorities. Insights into parasite biology, human immunity, and vector behavior will guide efforts to translate parasite and mosquito genome sequences into novel interventions.

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Nomadic or sessile: can Kupffer cells function as portals for malaria sporozoites to the liver?

Cited by 48 publications

References 97 publications

Purification of Plasmodium Sporozoites Enhances Parasite-Specific CD8 ⁺ T Cell Responses

Purification of Plasmodium Sporozoites Enhances Parasite-Specific CD8 ⁺ T Cell Responses

Plasmodium yoelii Sporozoites with Simultaneous Deletion of P52 and P36 Are Completely Attenuated and Confer Sterile Immunity against Infection

Malaria: progress, perils, and prospects for eradication

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Nomadic or sessile: can Kupffer cells function as portals for malaria sporozoites to the liver?

Cited by 48 publications

References 97 publications

Purification of Plasmodium Sporozoites Enhances Parasite-Specific CD8 + T Cell Responses

Purification of Plasmodium Sporozoites Enhances Parasite-Specific CD8 + T Cell Responses

Plasmodium yoelii Sporozoites with Simultaneous Deletion of P52 and P36 Are Completely Attenuated and Confer Sterile Immunity against Infection

Malaria: progress, perils, and prospects for eradication

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Purification of Plasmodium Sporozoites Enhances Parasite-Specific CD8 ⁺ T Cell Responses

Purification of Plasmodium Sporozoites Enhances Parasite-Specific CD8 ⁺ T Cell Responses