sporozoites, the mosquito-transmitted forms of the malaria parasite, first infect the liver for an initial round of replication before the emergence of pathogenic blood stages. Sporozoites represent ...attractive targets for antimalarial preventive strategies, yet the mechanisms of parasite entry into hepatocytes remain poorly understood. Here we show that the two main species causing malaria in humans,
and
, rely on two distinct host cell surface proteins, CD81 and the Scavenger Receptor BI (SR-BI), respectively, to infect hepatocytes. By contrast, CD81 and SR-BI fulfil redundant functions during infection by the rodent parasite
. Genetic analysis of sporozoite factors reveals the 6-cysteine domain protein P36 as a major parasite determinant of host cell receptor usage. Our data provide molecular insights into the invasion pathways used by different malaria parasites to infect hepatocytes, and establish a functional link between a sporozoite putative ligand and host cell receptors.
Deciphering the mechanisms by which
parasites develop inside hepatocytes is an important step toward the understanding of malaria pathogenesis. We propose that the nature and the magnitude of the ...inflammatory response in the liver are key for the establishment of the infection. Here, we used mice deficient in the multidrug resistance-2 gene (Mdr2
)-encoded phospholipid flippase leading to the development of liver inflammation. Infection of Mdr2
mice with
ANKA (
ANKA) sporozoites (SPZ) resulted in the blockade of hepatic exo-erythrocytic forms (EEFs) with no further development into blood stage parasites. Interestingly, cultured primary hepatocytes from mutant and wild-type mice are equally effective in supporting EEF development. The abortive infection resulted in a long-lasting immunity in Mdr2
mice against infectious SPZ where neutrophils and IL-6 appear as key effector components along with CD8
and CD4
effector and central memory T cells. Inflammation-induced breakdown of liver tolerance promotes anti-parasite immunity and provides new approaches for the design of effective vaccines against malaria disease.
Plasmodium sporozoites are transmitted to a mammalian host during blood feeding by an infected mosquito and invade hepatocytes for initial replication of the parasite into thousands of ...erythrocyte-invasive merozoites. Here we report that the B9 protein, a member of the 6-cysteine domain protein family, is secreted from sporozoite micronemes and is required for productive invasion of hepatocytes. The N-terminus of B9 forms a beta-propeller domain structurally related to CyRPA, a cysteine-rich protein forming an essential invasion complex in Plasmodium falciparum merozoites. The beta-propeller domain of B9 is essential for sporozoite infectivity and interacts with the 6-cysteine proteins P36 and P52 in a heterologous expression system. Our results suggest that, despite using distinct sets of parasite and host entry factors, Plasmodium sporozoites and merozoites may share common structural modules to assemble protein complexes for invasion of host cells.
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•Infectious Plasmodium sporozoites express the 6-cys protein B9•B9 is secreted from a specific subset of micronemes•B9 is required for sporozoite productive invasion of hepatocytes•B9 contains an essential CyRPA-like beta-propeller domain
Microbiology; Microbiology parasite; Molecular microbiology
Background:
An increased incidence of second primary malignancies (SPM) is described in chronic lymphocytic leukemia (CLL). Current hypothesis to explain this phenomenon mainly relies on ...immunosuppression conferred by both CLL itself and CLL treatment. The imputability of fludarabine has been long recognized but the risk associated with monoclonal antibodies, especially rituximab recently shown to improve overall survival in CLL when combined with fludarabine and cyclophosphamide (FC), remains unknown.
Materials and methods:
We conducted a retrospective study of the incidence of secondary cancers in 1255 CLL patients diagnosed since 1980 in the University Hospital of Lille to better characterize the possible risk of SPM associated with rituximab
Results:
Of 1255 patients, 651 (52%) received therapy including rituximab (38%), FC (26.7%), F alone (22.4%), chlorambucil (27.5%), alemtuzumab (15.5%) and bendamustine (9.3%). Rituximab was given either in combination with FC (27.5%), other chemotherapy (2.6%) or as a single-agent (3.5%). There was no significant difference in terms of age (58 versus 62 years), gender, Binet stage, cytogenetic abnormalities and number of regimen received between patients treated with or without rituximab. Median follow-up was 6 years for all patients (range 2-23), 4.8 years (range, 2-8) since initiation of therapy for patients treated without rituximab and 3.6 years (range, 0.2-11) for patients who received rituximab. Median overall survival (OS) was 18 years for patients treated with R-chemotherapy versus 11 years for patients treated with chemotherapy alone (p<0,001). Of 1255 patients, 21.5% were diagnosed with SPM. The incidence of SPM was 17.1% in patients who did not receive treatment compared to 10% in those treated. Among treated patients, the incidence of SPM was significantly higher (19% v 2%) in patients who received rituximab (p <0.001). SPM incidence was increased after R-FC (24.4%), FC (10.5%) compared to other regimen (p<0,001) (table1). Most frequent SPM were skin (25%)-and urologic cancers (23%). Median onset of SPM was 5 years (range, 2-20) without rituximab and 2 years (range, 1-7) with rituximab.
Table 1Incidence of SPMpTreatment, %- Purine analogs- FC- RFC- Chlorambucil- Bendamustine- Alemtuzumab- CorticothŽrapie- 1,9 10,5* 24,4* 4,9 0 3,5 0<0,001
Conclusion:
In this large single center retrospective study, we found an earlier and significantly increased incidence of SPM, mainly skin cancers, in CLL patients treated with R-chemotherapy compared to those given chemotherapy alone. It remains to be determined whether this increased SPM incidence is a due to a direct toxicity of rituximab or merely a collateral consequence of improved OS observed after rituximab.
Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Pierre Fabre: Membership on an entity's Board of Directors or advisory committees. Cazin:ROCHE: Consultancy; MUNDIPHARMA: Honoraria, Research Funding; NOVARTIS: Honoraria; GILEAD,: Honoraria. Morschhauser:Genentech Inc./Roche: Other: Advisory boards.
With the increase of international travel and development of insecticide resistance, a reemergence of the bed bug has been observed since the 2000's and becoming a worldwide public health problem. ...Hospital and other medical settings haven't been spared while the cases reported remains limited. However, there is no specific recommendation for the healthcare settings emanating from learned society.
We report our experience with a bed bug infestation of a medical unit, in the French University Hospital Center of Brest, caused by the admission of a patient carrier in October 2020. We described the practical methods we used to control bed bugs infestation, we evaluated the cost of this episode and we created a specific procedure to take care of the patients at risk or known carrier of bed bugs.
The decision to close the unit for a global treatment was taken after the investigations using a sniffing dog revealed that 4 rooms were infested. The closure lasted 24 days. We estimated the total cost of the infestation to approximately 400 000 US dollars. No other wave of infestation occurred. We created a specific protocol of care for patient known carrier or at risk of carriage of bed bug to graduate strategy of control.
Bed bugs infestation in Health facilities has a major impact on the care of patients and relevant economic consequences. Prevention and education policies are an essential starting point to response to the scale of the phenomenon.
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