Immune effector mechanisms in malaria: An update focusing on human immunity

Moormann, Ann M.; Nixon, Christina E.; Forconi, Catherine S.

doi:10.1111/pim.12628

Cited by 21 publications

(17 citation statements)

References 164 publications

(289 reference statements)

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“…Primary malaria infection induces CD4+ T cell differentiation into CXCR+ T follicular (Tfh) cells to provide B cell help and the highly proliferative Vγ9+Vδ2+ T cells produce high levels of IFN-γ (80). Production of pro-inflammatory cytokines and chemokines such as IL-1β, IL-6, IL-8, IL-12, IFN-γ, and TNF induce fever and other signs and symptoms in previously unexposed individuals resulting in severe and fatal malaria (81).…”

Section: Malaria Co-infectionmentioning

confidence: 99%

Immunological Considerations for Schistosoma Vaccine Development: Transitioning to Endemic Settings

et al. 2021

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Despite mass drug administration programmes with praziquantel, the prevalence of schistosomiasis remains high. A vaccine is urgently needed to control transmission of this debilitating disease. As some promising schistosomiasis vaccine candidates are moving through pre-clinical and clinical testing, we review the immunological challenges that these vaccine candidates may encounter in transitioning through the clinical trial phases in endemic settings. Prior exposure of the target population to schistosomes and other infections may impact vaccine response and efficacy and therefore requires considerable attention. Schistosomes are known for their potential to induce T-reg/IL-10 mediated immune suppression in populations which are chronically infected. Moreover, endemicity of schistosomiasis is focal whereby target and trial populations may exhibit several degrees of prior exposure as well as in utero exposure which may increase heterogeneity of vaccine responses. The age dependent distribution of exposure and development of acquired immunity, and general differences in the baseline immunological profile, adds to the complexity of selecting suitable trial populations. Similarly, prior or concurrent infections with other parasitic helminths, viral and bacterial infections, may alter immunological responses. Consequently, treatment of co-infections may benefit the immunogenicity of vaccines and may be considered despite logistical challenges. On the other hand, viral infections leave a life-long immunological imprint on the human host. Screening for serostatus may be needed to facilitate interpretation of vaccine responses. Co-delivery of schistosome vaccines with PZQ is attractive from a perspective of implementation but may complicate the immunogenicity of schistosomiasis vaccines. Several studies have reported PZQ treatment to induce both transient and long-term immuno-modulatory effects as a result of tegument destruction, worm killing and subsequent exposure of worm antigens to the host immune system. These in turn may augment or antagonize vaccine immunogenicity. Understanding the complex immunological interactions between vaccine, co-infections or prior exposure is essential in early stages of clinical development to facilitate phase 3 clinical trial design and implementation policies. Besides well-designed studies in different target populations using schistosome candidate vaccines or other vaccines as models, controlled human infections could also help identify markers of immune protection in populations with different disease and immunological backgrounds.

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Section: Malaria Co-infectionmentioning

confidence: 99%

Immunological Considerations for Schistosoma Vaccine Development: Transitioning to Endemic Settings

et al. 2021

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“…The immune system is a highly regulated and balanced system with neutrophils, macrophages, and NK cells acting against protozoan parasites by innate and adaptive immune responses. Innate immune cells together with dendritic cells play a vital role in the induction of T- and B-cell mediated adaptive immune responses by producing different pro-inflammatory (IL-1β, IL-6, IL-8, IL-12, IL-17, IFN-γ, and TNF-α) and anti-inflammatory (TGF-β, IL-4, IL-5, IL-10, and IL-13) cytokines that cause clinical symptoms, together resulting in parasite eradication and ultimately return to immune homeostasis [ 13 , 19 , 20 ]. These anti-parasite responses may affect the delicate immune balance between EBV and its host [ 6 , 7 , 11 , 14 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

Quantitative cytokine level of TNF-α, IFN-γ, IL-10, TGF-β and circulating Epstein-Barr virus DNA load in individuals with acute Malaria due to P. falciparum or P. vivax or double infection in a Malaria endemic region in Indonesia

et al. 2021

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Plasmodium falciparum Malaria and Epstein-Barr Virus (EBV) infection are risk factors in the development of Burkitt’s lymphoma. In Indonesia, 100% of the population is persistently infected with EBV early in life and at risk of developing EBV-linked cancers. Currently, 10.7 million people in Indonesia are living in Malaria-endemic areas. This cross-sectional study was initiated to investigate how acute Malaria dysregulates immune control over latent EBV infection. Using blood and plasma samples of 68 patients with acute Malaria and 27 healthy controls, we measured the level of parasitemia for each plasmodium type (P. falciparum, P. vivax, and mixed) by microscopy and rapid test. The level of 4 regulatory cytokines was determined by quantitative ELISA and the level of circulating EBV genome by real-time PCR targeting the single copy EBNA-1 sequence. All Plasmodium-infected cases had high-level parasitemia (>1000 parasites/ul blood) except for one case. EBV-DNA levels were significantly more elevated in P. falciparum and P. vivax infections (P<0.05) compared to controls. EBV-DNA levels were not related to age, gender, Malaria symptoms, or plasmodium type. TNF-α and IL-10 levels were increased in Malaria cases versus controls, but IFN-γ and TGF- β levels were comparable between the groups. Only TNF-α levels in P. falciparum cases showed a clear correlation with elevated EBV DNA levels (R2 = 0.8915). This is the first study addressing the relation between EBV (re)activation and cytokine responses during acute Malaria, revealing a clear correlation between pro-inflammatory cytokine TNF-α and EBV-DNA levels, specifically in P. falciparum cases, suggesting this cytokine to be key in dysregulating EBV homeostasis during acute P. falciparum Malaria.

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“…Expression of all CD18/CD11 a/b/c as well as CD16a, CD16b, CD32a, CD32b and Perforin 2 suggests a multifaceted involvement of antibody opsonization in the killing capacity of CD56 neg CD16 pos NK cells. P. falciparum induces a broad range of antibodies directed against the many parasite antigens that are able to trigger ADCC and ADRB (Moormann et al, 2019). Another important component for killing target cells is complement.…”

Section: Discussionmentioning

confidence: 99%

A New Hope for CD56negCD16pos NK Cells as Unconventional Cytotoxic Mediators: An Adaptation to Chronic Diseases

Forconi

Oduor

Oluoch

et al. 2020

Front. Cell. Infect. Microbiol.

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Natural Killer (NK) cells play an essential role in antiviral and anti-tumoral immune responses. In peripheral blood, NK cells are commonly classified into two major subsets: CD56 bright CD16 neg and CD56 dim CD16 pos despite the characterization of a CD56 neg CD16 pos subset 25 years ago. Since then, several studies have described the prevalence of an CD56 neg CD16 pos NK cell subset in viral non-controllers as the basis for their NK cell dysfunction. However, the mechanistic basis for their cytotoxic impairment is unclear. Recently, using a strict flow cytometry gating strategy to exclude monocytes, we reported an accumulation of CD56 neg CD16 pos NK cells in Plasmodium falciparum malaria-exposed children and pediatric cancer patients diagnosed with endemic Burkitt lymphoma (eBL). Here, we use live-sorted cells, histological staining, bulk RNA-sequencing and flow cytometry to confirm that this CD56 neg CD16 pos NK cell subset has the same morphological features as the other NK cell subsets and a similar transcriptional profile compared to CD56 dim CD16 pos NK cells with only 120 genes differentially expressed (fold change of 1.5, p < 0.01 and FDR<0.05) out of 9235 transcripts. CD56 neg CD16 pos NK cells have a distinct profile with significantly higher expression of MPEG1 (perforin 2), FCGR3B (CD16b), FCGR2A, and FCGR2B (CD32A and B) as well as CD6, CD84, HLA-DR, LILRB1/2, and PDCD1 (PD-1), whereas Interleukin 18 (IL18) receptor genes (IL18RAP and IL18R1), cytotoxic genes such as KLRF1 (NKp80) and NCR1 (NKp46), and inhibitory HAVCR2 (TIM-3) are significantly down-regulated compared to CD56 dim CD16 pos NK cells. Together, these data confirm that CD56 neg CD16 pos cells are legitimate NK cells, yet their transcriptional and protein expression profiles suggest their cytotoxic potential is mediated by pathways reliant on antibodies such as antibody-dependent cell cytotoxicity (ADCC), antibody-dependent respiratory burst (ADRB), and enhanced by complement receptor 3 (CR3) and FAS/FASL interaction. Our findings support the premise that chronic diseases induce NK cell Forconi et al. New Hope for CD56 neg CD16 pos NK Cells modifications that circumvent proinflammatory mediators involved in direct cytotoxicity. Therefore, individuals with such altered NK cell profiles may respond differently to NK-mediated immunotherapies, infections or vaccines depending on which cytotoxic mechanisms are being engaged.

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Immune effector mechanisms in malaria: An update focusing on human immunity

Cited by 21 publications

References 164 publications

Immunological Considerations for Schistosoma Vaccine Development: Transitioning to Endemic Settings

Immunological Considerations for Schistosoma Vaccine Development: Transitioning to Endemic Settings

Quantitative cytokine level of TNF-α, IFN-γ, IL-10, TGF-β and circulating Epstein-Barr virus DNA load in individuals with acute Malaria due to P. falciparum or P. vivax or double infection in a Malaria endemic region in Indonesia

A New Hope for CD56negCD16pos NK Cells as Unconventional Cytotoxic Mediators: An Adaptation to Chronic Diseases

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