Crystal structure of a hypothetical protein from Giardia lamblia. Corrigendum.

The name of one of the authors in Beard et al. [(2022), Acta Cryst. F78, 59-65] is corrected.

Crystal structure of a hypothetical protein from Giardia lamblia.

Giardiasis is the most prevalent diarrheal disease globally and affects humans and animals. It is a significant problem in developing countries, the number one cause of travelers' diarrhea and affects children and immunocompromised individuals, especially HIV-infected individuals. Giardiasis is treated with antibiotics (tinidazole and metronidazole) that are also used for other infections such as trichomoniasis.

Multinomial modelling of TB/HIV co-infection yields a robust predictive signature and generates hypotheses about the HIV+TB+ disease state.

Background: Current diagnostics are inadequate to meet the challenges presented by co-infection with Mycobacterium tuberculosis (Mtb) and HIV, the leading cause of death for HIV-infected individuals. Improved characterization of Mtb/HIV coinfection as a distinct disease state may lead to better identification and treatment of affected individuals.

Methods: Four previously-published TB and HIV co-infection related datasets were used to train and validate multinomial machine learning classifiers that simultaneously predict TB and HIV status.

Next Generation Histology-Directed Imaging Mass Spectrometry Driven by Autofluorescence Microscopy.

Histology-directed imaging mass spectrometry (IMS) is a spatially targeted IMS acquisition method informed by expert annotation that provides rapid molecular characterization of select tissue structures. The expert annotations are usually determined on digital whole slide images of histological stains where the staining preparation is incompatible with optimal IMS preparation, necessitating serial sections: one for annotation, one for IMS. Registration is then used to align staining annotations onto the IMS tissue section.

The identification of inhibitory compounds of Rickettsia prowazekii methionine aminopeptidase for antibacterial applications.

Methionine aminopeptidase (MetAP) is a dinuclear metalloprotease responsible for the cleavage of methionine initiator residues from nascent proteins. MetAP activity is necessary for bacterial proliferation and is therefore a projected novel antibacterial target. A compound library consisting of 294 members containing metal-binding functional groups was screened against Rickettsia prowazekii MetAP to determine potential inhibitory motifs.

Sooty mangabey genome sequence provides insight into AIDS resistance in a natural SIV host.

In contrast to infections with human immunodeficiency virus (HIV) in humans and simian immunodeficiency virus (SIV) in macaques, SIV infection of a natural host, sooty mangabeys (Cercocebus atys), is non-pathogenic despite high viraemia. Here we sequenced and assembled the genome of a captive sooty mangabey. We conducted genome-wide comparative analyses of transcript assemblies from C.

Plasmodium yoelii S4/CelTOS is important for sporozoite gliding motility and cell traversal.

Gliding motility and cell traversal by the Plasmodium ookinete and sporozoite invasive stages allow penetration of cellular barriers to establish infection of the mosquito vector and mammalian host, respectively. Motility and traversal are not observed in red cell infectious merozoites, and we have previously classified genes that are expressed in sporozoites but not merozoites (S genes) in order to identify proteins involved in these processes. The S4 gene has been described as criticaly involved in Cell Traversal for Ookinetes and Sporozoites (CelTOS), yet knockout parasites (s4/celtos¯) do not generate robust salivary gland sporozoite numbers, precluding a thorough analysis of S4/CelTOS function during host infection.

The Promise of Systems Biology Approaches for Revealing Host Pathogen Interactions in Malaria.

Despite global eradication efforts over the past century, malaria remains a devastating public health burden, causing almost half a million deaths annually (WHO, 2016). A detailed understanding of the mechanisms that control malaria infection has been hindered by technical challenges of studying a complex parasite life cycle in multiple hosts. While many interventions targeting the parasite have been implemented, the complex biology of poses a major challenge, and must be addressed to enable eradication.

Mycobacterium tuberculosis Rv3651 is a triple sensor-domain protein.

The genome of the human pathogen Mycobacterium tuberculosis (Mtb) encodes ∼4,400 proteins, but one third of them have unknown functions. We solved the crystal structure of Rv3651, a hypothetical protein with no discernible similarity to proteins with known function. Rv3651 has a three-domain architecture that combines one cGMP-specific phosphodiesterases, adenylyl cyclases and FhlA (GAF) domain and two Per-ARNT-Sim (PAS) domains.

Identifying host regulators and inhibitors of liver stage malaria infection using kinase activity profiles.

Plasmodium parasites have extensive needs from their host hepatocytes during the obligate liver stage of infection, yet there remains sparse knowledge of specific host regulators. Here we assess 34 host-targeted kinase inhibitors for their capacity to eliminate Plasmodium yoelii-infected hepatocytes. Using pre-existing activity profiles of each inhibitor, we generate a predictive computational model that identifies host kinases, which facilitate Plasmodium yoelii liver stage infection.

A Global Survey of ATPase Activity in Asexual Blood Stages and Gametocytes.

Effective malaria control and elimination in hyperendemic areas of the world will require treatment of the () blood stage that causes disease as well as the gametocyte stage that is required for transmission from humans to the mosquito vector. Most currently used therapies do not kill gametocytes, a highly specialized, non-replicating sexual parasite stage. Further confounding next generation drug development against is the unknown metabolic state of the gametocyte and the lack of known biochemical activity for most parasite gene products in general.

Comprehensive definition of human immunodominant CD8 antigens in tuberculosis.

Despite widespread use of the Bacillus Calmette-Guerin vaccine, tuberculosis, caused by infection with , remains a leading cause of morbidity and mortality worldwide. As CD8 T cells are critical to tuberculosis host defense and a phase 2b vaccine trial of modified vaccinia Ankara expressing Ag85a that failed to demonstrate efficacy, also failed to induce a CD8 T cell response, an effective tuberculosis vaccine may need to induce CD8 T cells. However, little is known about CD8, as compared to CD4, antigens in tuberculosis.

An indicator cell assay for blood-based diagnostics.

We have established proof of principle for the Indicator Cell Assay Platform™ (iCAP™), a broadly applicable tool for blood-based diagnostics that uses specifically-selected, standardized cells as biosensors, relying on their innate ability to integrate and respond to diverse signals present in patients' blood. To develop an assay, indicator cells are exposed in vitro to serum from case or control subjects and their global differential response patterns are used to train reliable, disease classifiers based on a small number of features. In a feasibility study, the iCAP detected pre-symptomatic disease in a murine model of amyotrophic lateral sclerosis (ALS) with 94% accuracy (p-Value = 3.

Structure of acid deoxyribonuclease.

Deoxyribonuclease II (DNase II) is also known as acid deoxyribonuclease because it has optimal activity at the low pH environment of lysosomes where it is typically found in higher eukaryotes. Interestingly, DNase II has also been identified in a few genera of bacteria and is believed to have arisen via horizontal transfer. Here, we demonstrate that recombinant Burkholderia thailandensis DNase II is highly active at low pH in the absence of divalent metal ions, similar to eukaryotic DNase II.

Ligand co-crystallization of aminoacyl-tRNA synthetases from infectious disease organisms.

Aminoacyl-tRNA synthetases (aaRSs) charge tRNAs with their cognate amino acid, an essential precursor step to loading of charged tRNAs onto the ribosome and addition of the amino acid to the growing polypeptide chain during protein synthesis. Because of this important biological function, aminoacyl-tRNA synthetases have been the focus of anti-infective drug development efforts and two aaRS inhibitors have been approved as drugs. Several researchers in the scientific community requested aminoacyl-tRNA synthetases to be targeted in the Seattle Structural Genomics Center for Infectious Disease (SSGCID) structure determination pipeline.

Towards functional antibody-based vaccines to prevent pre-erythrocytic malaria infection.

An effective malaria vaccine would be considered a milestone of modern medicine, yet has so far eluded research and development efforts. This can be attributed to the extreme complexity of the malaria parasites, presenting with a multi-stage life cycle, high genome complexity and the parasite's sophisticated immune evasion measures, particularly antigenic variation during pathogenic blood stage infection. However, the pre-erythrocytic (PE) early infection forms of the parasite exhibit relatively invariant proteomes, and are attractive vaccine targets as they offer multiple points of immune system attack.

Malaria Parasite Liver Infection and Exoerythrocytic Biology.

In their infection cycle, malaria parasites undergo replication and population expansions within the vertebrate host and the mosquito vector. Host infection initiates with sporozoite invasion of hepatocytes, followed by a dramatic parasite amplification event during liver stage parasite growth and replication within hepatocytes. Each liver stage forms up to 90,000 exoerythrocytic merozoites, which are in turn capable of initiating a blood stage infection.

Rickettsia prowazekii methionine aminopeptidase as a promising target for the development of antibacterial agents.

Methionine aminopeptidase (MetAP) is a class of ubiquitous enzymes essential for the survival of numerous bacterial species. These enzymes are responsible for the cleavage of N-terminal formyl-methionine initiators from nascent proteins to initiate post-translational modifications that are often essential to proper protein function. Thus, inhibition of MetAP activity has been implicated as a novel antibacterial target.

Complete attenuation of genetically engineered Plasmodium falciparum sporozoites in human subjects.

Immunization of humans with whole sporozoites confers complete, sterilizing immunity against malaria infection. However, achieving consistent safety while maintaining immunogenicity of whole parasite vaccines remains a formidable challenge. We generated a genetically attenuated Plasmodium falciparum (Pf) malaria parasite by deleting three genes expressed in the pre-erythrocytic stage (Pf p52/p36/sap1).

The s48/45 six-cysteine proteins: mediators of interaction throughout the Plasmodium life cycle.

During their life cycle Plasmodium parasites rely upon an arsenal of proteins that establish key interactions with the host and vector, and between the parasite sexual stages, with the purpose of ensuring infection, reproduction and proliferation. Among these is a group of secreted or membrane-anchored proteins known as the six-cysteine (6-cys) family. This is a small but important family with only 14 members thus far identified, each stage-specifically expressed during the parasite life cycle.

An expanding toolkit for preclinical pre-erythrocytic malaria vaccine development: bridging traditional mouse malaria models and human trials.

Malaria remains a significant public health burden with 214 million new infections and over 400,000 deaths in 2015. Elucidating relevant Plasmodium parasite biology can lead to the identification of novel ways to control and ultimately eliminate the parasite within geographic areas. Particularly, the development of an effective vaccine that targets the clinically silent pre-erythrocytic stages of infection would significantly augment existing malaria elimination tools by preventing both the onset of blood-stage infection/disease as well as spread of the parasite through mosquito transmission.

NADH dehydrogenase of Trypanosoma brucei is important for efficient acetate production in bloodstream forms.

In the slender bloodstream form, Trypanosoma brucei mitochondria are repressed for many functions. Multiple components of mitochondrial complex I, NADH:ubiquinone oxidoreductase, are expressed in this stage, but electron transfer through complex I is not essential. Here we investigate the role of the parasite's second NADH:ubiquinone oxidoreductase, NDH2, which is composed of a single subunit that also localizes to the mitochondrion.