A combined within-host and between-hosts modelling framework for the evolution of resistance to antimalarial drugs

The spread of drug resistance represents a significant challenge to many disease control efforts. The evolution of resistance is a complex process influenced by transmission dynamics between hosts as well as infection dynamics within these hosts. This study aims to investigate how these two processes combine to impact the evolution of resistance in malaria parasites. We introduce a stochastic modelling framework combining an epidemiological model of Plasmodium transmission and an explicit within-human infection model for two competing strains. Immunity, treatment and resistance costs are included in the within-host model. We show that the spread of resistance is generally less likely in areas of intense transmission, and therefore of increased competition between strains, an effect exacerbated when costs of resistance are higher. We also illustrate how treatment influences the spread of resistance, with a trade-off between slowing resistance and curbing disease incidence. We show that treatment coverage has a stronger impact on disease prevalence, whereas treatment efficacy primarily affects resistance spread, suggesting that coverage should constitute the primary focus of control efforts. Finally, we illustrate the importance of feedbacks between modelling scales. Overall, our results underline the importance of concomitantly modelling the evolution of resistance within and between hosts.

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Development of a Fluorescent Tool for Studying Legionella bozemanae Intracellular Infection

Microorganisms ◽

10.3390/microorganisms9020379 ◽

2021 ◽

Vol 9 (2) ◽

pp. 379

Author(s):

Breanne M. Head ◽

Christopher I. Graham ◽

Teassa MacMartin ◽

Yoav Keynan ◽

Ann Karen C. Brassinga

Keyword(s):

Growth Kinetics ◽

Legionella Pneumophila ◽

Fluorescent Protein ◽

Disease Incidence ◽

Acanthamoeba Castellanii ◽

Infection Model ◽

Intracellular Infection ◽

Green Fluorescent

Legionnaires’ disease incidence is on the rise, with the majority of cases attributed to the intracellular pathogen, Legionella pneumophila. Nominally a parasite of protozoa, L. pneumophila can also infect alveolar macrophages when bacteria-laden aerosols enter the lungs of immunocompromised individuals. L. pneumophila pathogenesis has been well characterized; however, little is known about the >25 different Legionella spp. that can cause disease in humans. Here, we report for the first time a study demonstrating the intracellular infection of an L. bozemanae clinical isolate using approaches previously established for L. pneumophila investigations. Specifically, we report on the modification and use of a green fluorescent protein (GFP)-expressing plasmid as a tool to monitor the L. bozemanae presence in the Acanthamoeba castellanii protozoan infection model. As comparative controls, L. pneumophila strains were also transformed with the GFP-expressing plasmid. In vitro and in vivo growth kinetics of the Legionella parental and GFP-expressing strains were conducted followed by confocal microscopy. Results suggest that the metabolic burden imposed by GFP expression did not impact cell viability, as growth kinetics were similar between the GFP-expressing Legionella spp. and their parental strains. This study demonstrates that the use of a GFP-expressing plasmid can serve as a viable approach for investigating Legionella non-pneumophila spp. in real time.

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Intranasal Infection of Ferrets with SARS-CoV-2 as a Model for Asymptomatic Human Infection

Viruses ◽

10.3390/v13010113 ◽

2021 ◽

Vol 13 (1) ◽

pp. 113

Author(s):

Helen E. Everett ◽

Fabian Z. X. Lean ◽

Alexander M. P. Byrne ◽

Pauline M. van Diemen ◽

Shelley Rhodes ◽

...

Keyword(s):

Genomic Sequence ◽

Humoral Response ◽

Asymptomatic Infection ◽

Human Infection ◽

Viral Rna ◽

Post Inoculation ◽

Upper Respiratory Tract ◽

Infection Dynamics ◽

Genomic Sequence Analysis ◽

Upper Respiratory

Ferrets were experimentally inoculated with SARS-CoV-2 (severe acute respiratory syndrome (SARS)-related coronavirus 2) to assess infection dynamics and host response. During the resulting subclinical infection, viral RNA was monitored between 2 and 21 days post-inoculation (dpi), and reached a peak in the upper respiratory cavity between 4 and 6 dpi. Viral genomic sequence analysis in samples from three animals identified the Y453F nucleotide substitution relative to the inoculum. Viral RNA was also detected in environmental samples, specifically in swabs of ferret fur. Microscopy analysis revealed viral protein and RNA in upper respiratory tract tissues, notably in cells of the respiratory and olfactory mucosae of the nasal turbinates, including olfactory neuronal cells. Antibody responses to the spike and nucleoprotein were detected from 21 dpi, but virus-neutralizing activity was low. A second intranasal inoculation (re-exposure) of two ferrets after a 17-day interval did not produce re-initiation of viral RNA shedding, but did amplify the humoral response in one animal. Therefore, ferrets can be experimentally infected with SARS-CoV-2 to model human asymptomatic infection.

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Rhinovirus induces MUC5AC in a human infection model and in vitro via NF- B and EGFR pathways

European Respiratory Journal ◽

10.1183/09031936.00026910 ◽

2010 ◽

Vol 36 (6) ◽

pp. 1425-1435 ◽

Cited By ~ 64

Author(s):

C. A. Hewson ◽

J. J. Haas ◽

N. W. Bartlett ◽

S. D. Message ◽

V. Laza-Stanca ◽

...

Keyword(s):

Human Infection ◽

Infection Model

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Aspergillus fumigatus. [Descriptions of Fungi and Bacteria].

IMI Descriptions of Fungi and Bacteria ◽

10.1079/dfb/20056400092 ◽

1966 ◽

Author(s):

A. H. S. Onions

Keyword(s):

Aspergillus Fumigatus ◽

Geographical Distribution ◽

Disease Incidence ◽

Allergic Bronchopulmonary Aspergillosis ◽

Wild Birds ◽

Mastoid Cavity ◽

Chronic Infections ◽

Free Living ◽

Haematogenous Spread ◽

Primary Focus

Abstract A description is provided for Aspergillus fumigatus. Information is included on the disease caused by the organism, its transmission, geographical distribution, and hosts. HOSTS: Common as a saprophyte in soil and fermenting vegetable matter. Pathogenic to mammals (including man), birds and insects. DISEASES: The most serious diseases caused by this fungus are the acute and chronic infections of the respiratory system (aspergillosis, aspergilloma) of man (Austwick, 1965; and many other references, e.g., RMVM 3, 677; 4, 316; 4, 549, 551) and animals (Ainsworth & Austwick, 1959; Austwick, 1965). It may also infect the cardiovascular, digestive, genital, musculoskeletal, nervous, and urinary systems, such infections usually following haematogenous spread of the pathogen from a primary focus in the lungs or air sacs. It is the most common cause of mycotic abortion in cattle (Ainsworth & Austwick, 1959; Austwick, RMVM 5, 660; Dijkstra; RMVM 5, 92) and less often in horses (Hensel et al. ; RMVM 4, 1227). Aspergillus fumigatus may also infect the ear (otomycosis) and mastoid cavity, the eye and sinuses (mycoses). Aspergillosis is a major disease of birds and is a cause of considerable losses in the poultry industry, particularly of very young birds (brooder pneumonia) (Vertinskii et al. ; RMVM 5, 758; Vallejo; 5, 940). It is also common in captive wild birds, especially water birds (Ainsworth & Rewell; RMVM 1, 2090; Dathe; 4, 1948; Saez; 4, 811), but reports of infections in free-living wild birds are more rare (Beer; RMVM 4, 2177; McDiarmid; 2, 1761; Rosen, 5, 558). A. fumigatus also invades eggs. Aspergillus fumigatus spores may induce allergic reactions in man, resulting in hay fever, asthma or allergic bronchopulmonary aspergillosis. It also produces toxins (Ainsworth & Austwick, 1959; Austwick, 1965). GEOGRAPHICAL DISTRIBUTION: World-wide. TRANSMISSION: Soil and air-borne. Disease incidence appears to be related to heavy infection from house dust, mouldy hay or straw, litter, or feeding stuffs (Austwick, 1965; Austwick, RMVM 5, 3b).

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A pneumococcal controlled human infection model in Malawi: Transfer of an established pneumococcal carriage model from Liverpool, UK to Blantyre, Malawi – A feasibility study

Wellcome Open Research ◽

10.12688/wellcomeopenres.15689.1 ◽

2020 ◽

Vol 5 ◽

pp. 25

Author(s):

Ben Morton ◽

Sarah Burr ◽

Kondwani Jambo ◽

Jamie Rylance ◽

Marc Y.R. Henrion ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

Feasibility Study ◽

Invasive Disease ◽

Community Acquired Pneumonia ◽

Human Infection ◽

Infection Model ◽

Endpoint Detection ◽

Pneumococcal Carriage ◽

Sampling Protocols ◽

Classical Culture

Streptococcus pneumoniae is the leading cause of morbidity and mortality due to community acquired pneumonia, bacterial meningitis and bacteraemia worldwide. Pneumococcal conjugate vaccines protect against invasive disease, but are expensive to manufacture, limited in serotype coverage, associated with serotype replacement and demonstrate reduced effectiveness against mucosal colonisation. As asymptomatic colonisation of the human nasopharynx is a prerequisite for pneumococcal disease, this is proposed as a marker for novel vaccine efficacy. Our team established a safe and reproducible pneumococcal controlled human infection model at Liverpool School of Tropical Medicine (LSTM). This has been used to test vaccine induced protection against nasopharyngeal carriage for ten years in over 1000 participants. We will transfer established standardised operating procedures from LSTM to Malawi and test in up to 36 healthy participants. Primary endpoint: detection of the inoculated pneumococci by classical culture from nasal wash recovered from the participants after pneumococcal challenge. Secondary endpoints: confirmation of robust clinical and laboratory methods for sample capture and processing. Tertiary endpoints: participant acceptability of study and methods. We will test three doses of pneumococcal inoculation (20,000, 80,000 and 160,000 colony forming units [CFUs] per naris) using a parsimonious study design intended to reduce unnecessary exposure to participants. We hypothesise that 80,000 CFUs will induce nasal colonisation in approximately half of participants per established LSTM practice. The aims of the feasibility study are: 1) Establish Streptococcus pneumoniae experimental human pneumococcal carriage in Malawi; 2) Confirm optimal nasopharyngeal pneumococcal challenge dose; 3) Confirm safety and measure potential symptoms; 4) Confirm sampling protocols and laboratory assays; 5) Assess feasibility and acceptability of consent and study procedures. Confirmation of pneumococcal controlled human infection model feasibility in Malawi will enable us to target pneumococcal vaccine candidates for an at-risk population who stand the most to gain from new and improved vaccine strategies.

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EPIDEMIOLOGICAL AND EPIZOOTIC ASPECT OF LEPTOSPIROSIS EVOLUTION IN TERNOPIL REGION

International Journal of Medicine and Medical Research ◽

10.11603/ijmmr.2413-6077.2016.1.6376 ◽

2016 ◽

Author(s):

N. A. Vasylieva ◽

Yu. A. Kravchuk

Keyword(s):

Infectious Diseases ◽

Disease Incidence ◽

Human Infection ◽

Farm Animals ◽

Natural Conditions ◽

Natural Reservoir ◽

Source Of Infection ◽

Regional Laboratory ◽

Dark Ground ◽

Different Sources

Background. Ternopil region is endemic on leptospirosis. Its natural conditions (slightly alkaline or alkaline soils, air temperature, sufficient rainfall) contribute to the existence of major natural reservoir of the pathogen – mouse-like rodents. In the region, different serovariants of leptospira are exuded by rodents and farm animals. Objective. The materials of the Department of Highly Infectious Diseases of Ternopil Regional Laboratory Centre of the State Sanitation and Epidemiological Service of Ukraine, Ternopil Regional Laboratory of Veterinary Medicine, Clinic of Infectious Diseases of TSMU were studied. Leptospiras were detected by dark ground microscopy (DFM) of blood of patients, trapped rodents and examined farm animals. Results. The circulating of pathogens between different sources (rodents, animals) and annual ��disease incidence evidences that new leptospira serovar are carried onto endemic area mostly by farm animals; humans are infected from them through the environment sometimes in 3-5 years intervals; the further diffusion to the new areas of this pathogen serovars in all kinds of the examined mouse-like rodents is noticed. It is established that farm animals and rodents are competing reservoirs. To predict the future epidemiological situation of leptospirosis among the humans and to improve its diagnosis the constant monitoring of the population, infection and leptospira carriage among mouse-like rodent and farm animals and expanding of the panel of diagnostic leptospira strains including new pathogen variants in animals is necessary. Conclusions. The development of additional reservoirs in animals, with circulating of other pathogen serovars among them, such as mouse-like rodents, which were previously absent in the main natural reservoir, cause the change of etiological structure in human leptospirosis at the endemic areas. The range of human leptospirosis pathogens and its further spreading among all kinds of rodents increased during our research. The results of detection of leptospirosis pathogens among the various contingents which were studied evidence that the farm animals and rodents are competing reservoirs that cause human infection through environment. KEY WORDS: leptospirosis, disease incidence, source of infection, rodents, farm animals.

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EnterotoxigenicE. colivirulence gene regulation in human infections

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1808982115 ◽

2018 ◽

Vol 115 (38) ◽

pp. E8968-E8976 ◽

Cited By ~ 15

Author(s):

Alexander A. Crofts ◽

Simone M. Giovanetti ◽

Erica J. Rubin ◽

Frédéric M. Poly ◽

Ramiro L. Gutiérrez ◽

...

Keyword(s):

Gene Expression ◽

Virulence Factor ◽

Virulence Gene ◽

Human Infection ◽

Anaerobic Growth ◽

Infection Model ◽

Low Oxygen ◽

Virulence Gene Expression ◽

Factor Expression

EnterotoxigenicEscherichia coli(ETEC) is a global diarrheal pathogen that utilizes adhesins and secreted enterotoxins to cause disease in mammalian hosts. Decades of research on virulence factor regulation in ETEC has revealed a variety of environmental factors that influence gene expression, including bile, pH, bicarbonate, osmolarity, and glucose. However, other hallmarks of the intestinal tract, such as low oxygen availability, have not been examined. Further, determining how ETEC integrates these signals in the complex host environment is challenging. To address this, we characterized ETEC’s response to the human host using samples from a controlled human infection model. We found ETEC senses environmental oxygen to globally influence virulence factor expression via the oxygen-sensitive transcriptional regulator fumarate and nitrate reduction (FNR) regulator. In vitro anaerobic growth replicates the in vivo virulence factor expression profile, and deletion offnrin ETEC strain H10407 results in a significant increase in expression of all classical virulence factors, including the colonization factor antigen I (CFA/I) adhesin operon and both heat-stable and heat-labile enterotoxins. These data depict a model of ETEC infection where FNR activity can globally influence virulence gene expression, and therefore proximity to the oxygenated zone bordering intestinal epithelial cells likely influences ETEC virulence gene expression in vivo. Outside of the host, ETEC biofilms are associated with seasonal ETEC epidemics, and we find FNR is a regulator of biofilm production. Together these data suggest FNR-dependent oxygen sensing in ETEC has implications for human infection inside and outside of the host.

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