Browsing by Author "Lorenzi, Hernan"

Now showing 1 - 6 of 6
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    [Letter to the editor] PCR prescreen for genotyping the Ts65Dn mouse model of Down syndrome
    (Future Medicine, 2018-04-03) Lorenzi, Hernan; Duvall, Nichole; Cherry, Sheila M.; Reeves, Roger H.; Roper, Randall J.; Biology, School of Science
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    A Molecular Signature in Blood Reveals a Role for p53 in Regulating Malaria-Induced Inflammation
    (Elsevier, 2019-10-15) Tran, Tuan M.; Guha, Rajan; Portugal, Silvia; Skinner, Jeff; Ongoiba, Aissata; Bhardwaj, Jyoti; Jones, Marcus; Moebius, Jacqueline; Venepally, Pratap; Doumbo, Safiatou; DeRiso, Elizabeth A.; Li, Shanping; Vijayan, Kamalakannan; Anzick, Sarah L.; Hart, Geoffrey T.; O’Connell, Elise M.; Doumbo, Ogobara K.; Kaushansky, Alexis; Alter, Galit; Felgner, Phillip L.; Lorenzi, Hernan; Kayentao, Kassoum; Traore, Boubacar; Kirkness, Ewen F.; Crompton, Peter D.; Medicine, School of Medicine
    Immunity that controls parasitemia and inflammation during Plasmodium falciparum (Pf) malaria can be acquired with repeated infections. A limited understanding of this complex immune response impedes the development of vaccines and adjunctive therapies. We conducted a prospective systems biology study of children who differed in their ability to control parasitemia and fever following Pf infection. By integrating whole-blood transcriptomics, flow-cytometric analysis, and plasma cytokine and antibody profiles, we demonstrate that a pre-infection signature of B cell enrichment; upregulation of T-helper type 1 (Th1) and Th2 cell-associated pathways, including interferon responses; and p53 activation associated with control of malarial fever and coordinated with Pf-specific IgG and Fc receptor activation to control parasitemia. Our hypothesis-generating approach identified host molecules that may contribute to differential clinical outcomes during Pf infection. As a proof of concept, we have shown that enhanced p53 expression in monocytes attenuated Plasmodium-induced inflammation and predicted protection from fever.
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    Susceptibility to febrile malaria is associated with an inflammatory gut microbiome
    (Research Square, 2024-04-04) Schmidt, Nathan; Van Den Ham, Kristin; Bower, Layne; Li, Shanping; Lorenzi, Hernan; Doumbo, Safiatou; Doumtabe, Didier; Kayentao, Kassoum; Ongoiba, Aissata; Traore, Boubacar; Crompton, Peter; Medicine, School of Medicine
    Malaria is a major public health problem, but many of the factors underlying the pathogenesis of this disease are not well understood. Here, we demonstrate in Malian children that susceptibility to febrile malaria following infection with Plasmodium falciparum is associated with the composition of the gut microbiome prior to the malaria season. Gnotobiotic mice colonized with the fecal samples of malaria-susceptible children had a significantly higher parasite burden following Plasmodium infection compared to gnotobiotic mice colonized with the fecal samples of malaria-resistant children. The fecal microbiome of the susceptible children was enriched for bacteria associated with inflammation, mucin degradation, gut permeability and inflammatory bowel disorders (e.g., Ruminococcus gauvreauii, Ruminococcus torques, Dorea formicigenerans, Dorea longicatena, Lachnoclostridium phocaeense and Lachnoclostridium sp. YL32). However, the susceptible children also had a greater abundance of bacteria known to produce anti-inflammatory short-chain fatty acids and those associated with favorable prognosis and remission following dysbiotic intestinal events (e.g., Anaerobutyricum hallii, Blautia producta and Sellimonas intestinalis). Metabolomics analysis of the human fecal samples corroborated the existence of inflammatory and recovery-associated features within the gut microbiome of the susceptible children. There was an enrichment of nitric oxide-derived DNA adducts (deoxyinosine and deoxyuridine) and long-chain fatty acids, the absorption of which has been shown to be inhibited by inflamed intestinal epithelial cells, and a decrease in the abundance of mucus phospholipids. Nevertheless, there were also increased levels of pseudouridine and hypoxanthine, which have been shown to be regulated in response to cellular stress and to promote recovery following injury or hypoxia. Overall, these results indicate that the gut microbiome may contribute malaria pathogenesis and suggest that therapies targeting intestinal inflammation could decrease malaria susceptibility.
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    The gut microbiome is associated with susceptibility to febrile malaria in Malian children
    (Springer Nature, 2024-11-05) Van Den Ham, Kristin M.; Bower, Layne K.; Li, Shanping; Lorenzi, Hernan; Doumbo, Safiatou; Doumtabe, Didier; Kayentao, Kassoum; Ongoiba, Aissata; Traore, Boubacar; Crompton, Peter D.; Schmidt, Nathan W.; Pediatrics, School of Medicine
    Malaria is a major public health problem, but many of the factors underlying the pathogenesis of this disease are not well understood, including protection from the development of febrile symptoms, which is observed in individuals residing in areas with moderate-to-high transmission by early adolescence. Here, we demonstrate that susceptibility to febrile malaria following Plasmodium falciparum infection is associated with the composition of the gut microbiome prior to the malaria season in 10-year-old Malian children, but not in younger children. Gnotobiotic mice colonized with the fecal samples of malaria-susceptible children were shown to have a significantly higher parasite burden following Plasmodium infection compared to gnotobiotic mice colonized with the fecal samples of malaria-resistant children. The fecal microbiome of the susceptible children was determined to be enriched for bacteria associated with inflammation, mucin degradation and gut permeability, and to have increased levels of nitric oxide-derived DNA adducts and lower levels of mucus phospholipids compared to the resistant children. Overall, these results indicate that the composition of the gut microbiome is associated with the prospective risk of febrile malaria in Malian children and suggest that modulation of the gut microbiome could decrease malaria morbidity in endemic areas.
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    Transcriptomic evidence for modulation of host inflammatory responses during febrile Plasmodium falciparum malaria
    (SpringerNature, 2016-08-10) Tran, Tuan M.; Jones, Marcus B.; Ongoiba, Aissata; Bijker, Else M.; Schats, Remko; Venepally, Pratap; Skinner, Jeff; Doumbo, Safiatou; Quinten, Edwin; Visser, Leo G.; Whalen, Elizabeth; Presnell, Scott; O’Connell, Elise M.; Kayentao, Kassoum; Doumbo, Ogobara K.; Chaussabel, Damien; Lorenzi, Hernan; Nutman, Thomas B.; Ottenhoff, Tom H. M.; Haks, Mariëlle C.; Traore, Boubacar; Kirkness, Ewen F.; Sauerwein, Robert W.; Crompton, Peter D.; Department of Medicine, IU School of Medicine
    Identifying molecular predictors and mechanisms of malaria disease is important for understanding how Plasmodium falciparum malaria is controlled. Transcriptomic studies in humans have so far been limited to retrospective analysis of blood samples from clinical cases. In this prospective, proof-of-principle study, we compared whole-blood RNA-seq profiles at pre-and post-infection time points from Malian adults who were either asymptomatic (n = 5) or febrile (n = 3) during their first seasonal PCR-positive P. falciparum infection with those from malaria-naïve Dutch adults after a single controlled human malaria infection (n = 5). Our data show a graded activation of pathways downstream of pro-inflammatory cytokines, with the highest activation in malaria-naïve Dutch individuals and significantly reduced activation in malaria-experienced Malians. Newly febrile and asymptomatic infections in Malians were statistically indistinguishable except for genes activated by pro-inflammatory cytokines. The combined data provide a molecular basis for the development of a pyrogenic threshold as individuals acquire immunity to clinical malaria.
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    Whole-blood transcriptomic signatures induced during immunization by chloroquine prophylaxis and Plasmodium falciparum sporozoites
    (Springer Nature, 2019-06-10) Tran, Tuan M.; Bijker, Else M.; Haks, Mariëlle C.; Ottenhoff, Tom H. M.; Visser, Leo; Schats, Remko; Venepally, Pratap; Lorenzi, Hernan; Crompton, Peter D.; Sauerwein, Robert W.; Medicine, School of Medicine
    A highly effective vaccine that confers sterile protection to malaria is urgently needed. Immunization under chemoprophylaxis with sporozoites (CPS) consistently confers high levels of protection in the Controlled Human Malaria infection (CHMI) model. To provide a broad, unbiased assessment of the composition and kinetics of direct ex vivo human immune responses to CPS, we profiled whole-blood transcriptomes by RNA-seq before and during CPS immunization and following CHMI challenge. Differential expression of genes enriched in modules related to T cells, NK cells, protein synthesis, and mitochondrial processes were detected in fully protected individuals four weeks after the first immunization. Non-protected individuals demonstrated transcriptomic changes after the third immunization and the day of treatment, with upregulation of interferon and innate inflammatory genes and downregulation of B-cell signatures. Protected individuals demonstrated more significant interactions between blood transcription modules compared to non-protected individuals several weeks after the second and third immunizations. These data provide insight into the molecular and cellular basis of CPS-induced immune protection from P. falciparum infection.