Malaria caused by the Plasmodium vivax parasite is a major global health burden. Immunity against blood-stage infection reduces parasitemia and disease severity. Duffy-binding protein (DBP) is the primary parasite protein responsible for the invasion of red blood cells and it is a leading subunit vaccine candidate. An effective vaccine, however, is still lacking despite decades of interest in DBP as a vaccine candidate. This review discusses the reasons for targeting DBP, the challenges associated with developing a vaccine, and modern structural vaccinology methods that could be used to create an effective DBP vaccine. Next-generation DBP vaccines have the potential to elicit a broadly protective immune response and provide durable and potent protection from P. vivax malaria.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has expanded into a global pandemic, with more than 220 million affected persons and almost 4.6 million deaths by 8 September 2021. In particular, Europe and the Americas have been heavily affected by high infection and death rates. In contrast, much lower infection rates and mortality have been reported generally in Africa, particularly in the sub-Saharan region (with the exception of the Southern Africa region). There are different hypotheses for this African paradox, including less testing, the young age of the population, genetic disposition, and behavioral and epidemiological factors. In the present review, we address different immunological factors and their correlation with genetic factors, pre-existing immune status, and differences in cytokine induction patterns. We also focus on epidemiological factors, such as specific medication coverage, helminth distribution, and malaria endemics in the sub-Saharan region. An analysis combining different factors is presented that highlights the central role of the NF-κB signaling pathway in the African paradox. Importantly, insights into the interplay of different factors with the underlying immune pathological mechanisms for COVID-19 can provide a better understanding of the disease and the development of new targets for more efficient treatment strategies.

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, including palbociclib, are approved to treat hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) and are associated with hematologic toxicity. African American women, who are underrepresented in CDK4/6 inhibitor clinical trials, may experience worse neutropenia because of benign ethnic neutropenia. The authors specifically investigated the hematologic safety of palbociclib in African American women with HR-positive/HER2-negative ABC.
PALINA was a single-arm, open-label, investigator-initiated study of palbociclib (125 mg daily; 21 days on and 7 days off) plus endocrine therapy (ET) in African American women who had HR-positive/HER2-negative ABC and a baseline absolute neutrophil count ≥1000/mm3 (ClinicalTrials.gov identifier NCT02692755). The primary outcome was the proportion of patients who completed 12 months of therapy without experiencing febrile neutropenia or treatment discontinuation because of neutropenia. Single nucleotide polymorphism analysis was used to assess Duffy polymorphism status.
Thirty-five patients received ≥1 dose of palbociclib plus ET; 19 had a Duffy null polymorphism (cytosine/cytosine). There were no reports of febrile neutropenia or permanent study discontinuation because of neutropenia. Significantly more patients with the Duffy null versus the wild-type variant had grade 3 and 4 neutropenia (72.2% vs 23.1%; P = .029) and required a palbociclib dose reduction (55.6% vs 7.7%; P = .008). Patients with the Duffy null versus the wild-type variant had lower overall relative dose intensity (mean ± SD, 81.89% ± 15.87 and 95.67% ± 5.89, respectively; P = .0026) and a lower clinical benefit rate (66.7% and 84.6%, respectively).
These findings suggest that palbociclib is well tolerated in African American women with HR-positive/HER2-negative ABC. Duffy null status may affect the incidence of grade 3 neutropenia, dose intensity, and possibly clinical benefit.

Interleukin-22 (IL-22) is a cytokine with important functions in host defense and inflammatory responses and has recently been suggested to play a role in immune-inflammatory system in the context of obesity and its metabolic consequences. The specific cellular targets and mechanisms of IL-22-mediated obesity are largely unknown however. We here identified a previously unknown subset of monocyte-derived Duffy antigen receptors for chemokines (DARC)+ macrophages in epididymal fat adipose tissue and found that they are preferentially recruited into the crown-like structures of adipose tissue in the mouse upon high fat diet-induced obesity. Importantly, DARC+ macrophages highly express the IL-22 receptor (IL-22Ra1). Exposure to recombinant IL-22 shifts macrophages to an alternative M2 polarization pathway and augments DARC expression via a STAT5b signaling axis. STAT5b directly binds to the DARC promoter and a STAT5 inhibitor abrogates the IL-22-mediated induction of DARC. These M2-like DARC+ subpopulations of monocytes/macrophages were elevated in obese db/db mice compared to WT lean mice. Furthermore, subsets of CD14+ and/or CD16+ monocytes/macrophages within human peripheral blood mononuclear cell populations express DARC and the prevalence of these subsets is enhanced by IL-22 stimuli. This suggested that IL-22 is a critical cytokine that promotes the infiltration of adipose tissue macrophages, that regulate inflammatory processes. Taken together, our present findings provide important insights into the molecular mechanism by which IL-22 signal modulates DARC expression in M2-like macrophages.

Malaria parasite erythrocytic stages comprise of repeated bursts of parasites via cyclical invasion of host erythrocytes using dedicated receptor-ligand interactions. A family of erythrocyte-binding proteins from Plasmodium knowlesi (Pk) and Plasmodium vivax (Pv) attach to human Duffy antigen receptor for chemokines (DARC) via their Duffy binding-like domains (DBLs) for invasion. Here we provide a novel, testable and overarching interaction model that rationalizes even contradictory pieces of evidence that have so far existed in the literature on Pk/Pv-DBL/DARC binding determinants. We further address the conundrum of how parasite-encoded Pk/Pv-DBLs recognize human DARC and collate evidence for two distinct DARC integration sites on Pk/Pv-DBLs.

This study aims to determine the relationship between Duffy antigen receptor for chemokines (DARC) and keloid pathogenesis. DARC expression was determined by immunohistochemistry, real-time PCR, and Western blot analysis. Cell proliferation was assessed by CCK-8 assay. Cell migration and invasion abilities were measured by the shift assay. Levels of CC chemokine ligand 2 (CCL2), CXC chemokine ligand 8 (CXCL8), and matrix metalloproteinase 2 (MMP2) were detected by real-time PCR and ELISA. Our results showed that DARC levels were elevated in human keloid fibroblasts. After knocking down DARC, cell proliferation was not altered, whereas the migration and invasion abilities of keloid fibroblasts were significantly elevated. Additionally, the mRNA expression levels of CCL2, CXCL8, and MMP2 were not influenced by DARC knockdown. However, the secretion of CCL2, but not CXCL8 or MMP2, was significantly increased after DARC knockdown. Our results suggest that DARC might inhibit the secretion of CCL2. Moreover, DARC knockdown increases the migration and invasion abilities of keloid fibroblasts.