scholarly journals Olfactory host entry supports herpesvirus recombination

2020 ◽  
Author(s):  
Wanxiaojie Xie ◽  
Kimberley Bruce ◽  
Helen E. Farrell ◽  
Philip G. Stevenson
Keyword(s):  
Salivary Gland ◽  
Lung Infection ◽  
Latent Virus ◽  
Murine Cytomegalovirus ◽  
Normal Host ◽  
New Hosts ◽  
Olfactory Cells ◽  
Lung Infections ◽  
Herpesvirus 4 ◽  
Virus Strains

AbstractHerpesvirus genomes record abundant recombination. Its impact on infection remains ill-defined. When co-infecting mice by the natural olfactory route, individually incapacitated Murid Herpesvirus-4 (MuHV-4) mutants routinely recombined to restore normal host colonization. Lung infection rescued much less well. Murine cytomegalovirus mutants deficient in salivary gland colonization also showed rescue via the nose but not the lungs. As nose and lung infections show similar spread, efficient recombination seemed specific to olfactory entry. Rescue of replication-deficient MuHV-4 implied co-infection of the first encountered cells, and this worked also with asynchronous inoculation, suggesting that latent virus could lie in wait for later reactivation. Inhaled MuHV-4 is commonly caught on respiratory mucus, which epithelial cilia push back towards the olfactory surface, and infection was correspondingly frequent at the anterior olfactory edge. Thus olfactory entry provides a general means for herpesviruses to meet.Author summaryInter-strain recombination allows viruses to optimise infection in diverse hosts. Many herpesviruses show past recombination. Yet they are ancient pathogens, so this past may be remote and recombination rare. Diverse herpesviruses enter new hosts via olfactory cells. We show that such entry routinely allows recombination between co-infecting virus strains, even when one strain cannot spread. Recombination was contrastingly rare after lung infection. Thus, entry via olfactory cells specifically supports frequent herpesvirus recombination.

scholarly journals Murine Cytomegalovirus Exploits Olfaction To Enter New Hosts

mBio ◽  
2016 ◽  
Vol 7 (2) ◽  
Author(s):  
Helen E. Farrell ◽  
Clara Lawler ◽  
Cindy S. E. Tan ◽  
Kate MacDonald ◽  
Kimberley Bruce ◽  
...  
Keyword(s):  
Murine Cytomegalovirus ◽  
Macrophage Infection ◽  
Herpes Simplex Virus 1 ◽  
Olfactory Neurons ◽  
Mucosal Surfaces ◽  
Systemic Spread ◽  
New Hosts ◽  
Herpesvirus 4 ◽  
Simplex Virus ◽  
Human Cmv

ABSTRACT  Viruses transmit via the environmental and social interactions of their hosts. Herpesviruses have colonized mammals since their earliest origins, suggesting that they exploit ancient, common pathways. Cytomegaloviruses (CMVs) are assumed to enter new hosts orally, but no site has been identified. We show by live imaging that murine CMV (MCMV) infects nasally rather than orally, both after experimental virus uptake and during natural transmission. Replication-deficient virions revealed the primary target as olfactory neurons. Local, nasal replication by wild-type MCMV was not extensive, but there was rapid systemic spread, associated with macrophage infection. A long-term, transmissible infection was then maintained in the salivary glands. The viral m131/m129 chemokine homolog, which influences tropism, promoted salivary gland colonization after nasal entry but was not required for entryper se. The capacity of MCMV to transmit via olfaction, together with previous demonstrations of experimental olfactory infection by murid herpesvirus 4 (MuHV-4) and herpes simplex virus 1 (HSV-1), suggest that this is a common, conserved route of mammalian herpesvirus entry.IMPORTANCECytomegaloviruses (CMVs) infect most mammals. Human CMV (HCMV) harms people with poor immune function and can damage the unborn fetus. It infects approximately 1% of live births. We lack a good vaccine. One problem is that how CMVs first enter new hosts remains unclear. Oral entry is often assumed, but the evidence is indirect, and no infection site is known. The difficulty of analyzing HCMV makes related animal viruses an important source of insights. Murine CMV (MCMV) infected not orally but nasally. Specifically, it targeted olfactory neurons. Viral transmission was also a nasal infection. Like HCMV, MCMV infected cells by binding to heparan, and olfactory surfaces display heparan to incoming viruses, whereas most other mucosal surfaces do not. These data establish a new understanding of CMV infections and a basis for infection control.

Olfactory entry promotes herpesvirus recombination

2021 ◽  
Author(s):  
Wanxiaojie Xie ◽  
Kimberley Bruce ◽  
Helen E. Farrell ◽  
Philip G. Stevenson
Keyword(s):  
Point Mutations ◽  
Murine Cytomegalovirus ◽  
Entry Site ◽  
Recombinant Viruses ◽  
Viral Loads ◽  
Show Evidence ◽  
Olfactory Cells ◽  
Herpesvirus 4 ◽  
Respiratory Epithelial ◽  
Human Herpesviruses

Herpesvirus genomes show abundant evidence of past recombination. Its functional importance is unknown. A key question is whether recombinant viruses can outpace the immunity induced by their parents to reach higher loads. We tested this by co-infecting mice with attenuated mutants of Murid Herpesvirus-4 (MuHV-4). Infection by the natural olfactory route routinely allowed mutant viruses to reconstitute wild-type genotypes and reach normal viral loads. Lung co-infections rescued much less well. Attenuated murine cytomegalovirus mutants similarly showed recombinational rescue via the nose but not the lungs. These infections spread similarly, so route-specific rescue implied that recombination occurred close to the olfactory entry site. Rescue of replication-deficient MuHV-4 confirmed this, showing that coinfection occurred in the first encountered olfactory cells. This worked even with asynchronous inoculation, implying that a defective virus can wait here for later rescue. Virions entering the nose get caught on respiratory mucus, which the respiratory epithelial cilia push back towards the olfactory surface. Early infection was correspondingly focussed on the anterior olfactory edge. Thus, by concentrating incoming infection into a small area, olfactory entry seems to promote functionally significant recombination. Importance All organisms depend on genetic diversity to cope with environmental change. Small viruses rely on frequent point mutations. This is harder for herpesviruses because they have larger genomes. Recombination provides another means of genetic optimization. Human herpesviruses often co-infect, and they show evidence of past recombination, but whether this is rare and incidental or functionally important is unknown. We showed that herpesviruses entering mice via the natural olfactory route meet reliably enough for recombination routinely to repair crippling mutations and restore normal viral loads. It appeared to occur in the first encountered olfactory cells and reflected a concentration of infection at the anterior olfactory edge. Thus, natural host entry incorporates a significant capacity for herpesvirus recombination.

scholarly journals Efficacy of SCH27899 in an Animal Model of Legionnaires' Disease Using Immunocompromised A/J Mice

2000 ◽  
Vol 44 (5) ◽  
pp. 1333-1336 ◽  
Author(s):  
Joan K. Brieland ◽  
David Loebenberg ◽  
Fred Menzel ◽  
Roberta S. Hare
Keyword(s):  
Animal Model ◽  
Murine Model ◽  
Legionella Pneumophila ◽  
Immunocompromised Host ◽  
Lung Infection ◽  
Cortisone Acetate ◽  
Contrast Administration ◽  
Once Daily ◽  
Legionnaires Disease ◽  
Lung Infections

ABSTRACT The efficacy of SCH27899, a new everninomicin antibiotic, against replicative Legionella pneumophila lung infections in an immunocompromised host was evaluated using a murine model of Legionnaires' disease. A/J mice were immunocompromised with cortisone acetate and inoculated intratracheally with L. pneumophilaserogroup 1 (105 CFU per mouse). At 24 h postinoculation, mice were administered either SCH27899 (6 to 60 mg/kg [MPK] intravenously) or a placebo once daily for 5 days, and mortality and intrapulmonary growth of L. pneumophila were assessed. In the absence of SCH27899, there was 100% mortality inL. pneumophila-infected mice, with exponential intrapulmonary growth of the bacteria. In contrast, administration of SCH27899 at a dose of ≥30 MPK resulted in ≥90% survival of infected mice, which was associated with inhibition of intrapulmonary growth ofL. pneumophila. In subsequent studies, the efficacy of SCH27899 was compared to ofloxacin (OFX) and azithromycin (AZI). Administration of SCH27899, OFX, or AZI at a dose of ≥30 MPK once daily for 5 days resulted in ≥85% survival of infected mice and inhibition of intrapulmonary growth of the bacteria. However, L. pneumophila CFU were recovered in lung homogenates following cessation of therapy with all three antibiotics. These studies demonstrate that SCH27899 effectively prevents fatal replicativeL. pneumophila lung infection in immunocompromised A/J mice by inhibition of intrapulmonary growth of the bacteria. However, in this murine model of pulmonary legionellosis, SCH27899, like OFX and AZI, was bacteriostatic.

scholarly journals Murine Cytomegalovirus Spread Depends on the Infected Myeloid Cell Type

2019 ◽  
Vol 93 (15) ◽  
Author(s):  
Helen E. Farrell ◽  
Kimberley Bruce ◽  
Clara Lawler ◽  
Philip G. Stevenson
Keyword(s):  
Dendritic Cells ◽  
Salivary Gland ◽  
Salivary Glands ◽  
Olfactory Epithelium ◽  
Ex Vivo ◽  
Myeloid Cells ◽  
Murine Cytomegalovirus ◽  
Cell Type ◽  
High Endothelial Venules ◽  
Brown Adipose

ABSTRACTCytomegaloviruses (CMVs) colonize blood-borne myeloid cells. Murine CMV (MCMV) spreads from the lungs via infected CD11c+cells, consistent with an important role for dendritic cells (DC). We show here that MCMV entering via the olfactory epithelium, a natural transmission portal, also spreads via infected DC. They reached lymph nodes, entered the blood via high endothelial venules, and then entered the salivary glands, driven by constitutive signaling of the viral M33 G protein-coupled receptor (GPCR). Intraperitoneal infection also delivered MCMV to the salivary glands via DC. However, it also seeded F4/80+infected macrophages to the blood; they did not enter the salivary glands or require M33 for extravasation. Instead, they seeded infection to a range of other sites, including brown adipose tissue (BAT). Peritoneal cells infectedex vivothen adoptively transferred showed similar cell type-dependent differences in distribution, with abundant F4/80+cells in BAT and CD11c+cells in the salivary glands. BAT colonization by CMV-infected cells was insensitive to pertussis toxin inhibition of the GPCR signaling through Gi/osubstrate, whereas salivary gland colonization was sensitive. Since salivary gland infection required both M33 and Gi/o-coupled signaling, whereas BAT infection required neither, these migrations were mechanistically distinct. MCMV spread from the lungs or nose depended on DC, controlled by M33. Infecting other monocyte populations resulted in unpredictable new infections.IMPORTANCECytomegaloviruses (CMVs) spread through the blood by infecting monocytes, and this can lead to disease. With murine CMV (MCMV) we can track infected myeloid cells and so understand how CMVs spread. Previous experiments have injected MCMV into the peritoneal cavity. MCMV normally enters mice via the olfactory epithelium. We show that olfactory infection spreads via dendritic cells, which MCMV directs to the salivary glands. Peritoneal infection similarly reached the salivary glands via dendritic cells. However, it also infected other monocyte types, and they spread infection to other tissues. Thus, infecting the “wrong” monocytes altered virus spread, with potential to cause disease. These results provide a basis for understanding how the monocyte types infected by human CMV might promote different infection outcomes.

Staphylococci in a Mental Hospital

1964 ◽  
Vol 110 (465) ◽  
pp. 240-243
Author(s):  
S. S. Reza
Keyword(s):  
Staphylococcus Aureus ◽  
Mental Hospital ◽  
Lung Infection ◽  
Skin Lesions ◽  
Carrier Rate ◽  
Bacteriological Study ◽  
Nasal Carrier ◽  
Lung Infections ◽  
Institutionalized Patients

The present study on the acquisition of Staphylococcus aureus by patients during their stay in a mental hospital, and the nasal carrier rate in the institutionalized patients, was prompted by the fact that in 1959 and 1960 193 out of a total of 407 deaths in Napsbury Hospital were due to lung infection, and that a bacteriological study of 45 unselected cases at necropsy in 1960 had suggested that the fatal lung infections were predominantly staphylococcal (Table I). The incidence of staphylococcal skin lesions, however, remained low, and only 147 cases of this kind were reported during 1959 and 1960 (4 per cent. per annum of the population) (Table II).

scholarly journals Comparative Analysis of Plant and Animal Models for Characterization of Burkholderia cepacia Virulence

2003 ◽  
Vol 71 (9) ◽  
pp. 5306-5313 ◽  
Author(s):  
Steve P. Bernier ◽  
Laura Silo-Suh ◽  
Donald E. Woods ◽  
Dennis E. Ohman ◽  
Pamela A. Sokol
Keyword(s):  
Comparative Analysis ◽  
Animal Models ◽  
Burkholderia Cepacia ◽  
Parent Strain ◽  
Lung Infection ◽  
Infection Model ◽  
Burkholderia Multivorans ◽  
Lung Infections

ABSTRACT A simple alfalfa model was developed as an alternative infection model for virulence studies of the Burkholderia cepacia complex. Symptoms of disease were observed in wounded alfalfa seedlings within 7 days following inoculation of 101 to 105 CFU of most strains of the B. cepacia complex. Strains from seven genomovars of the B. cepacia complex were tested for virulence in the alfalfa model, and the degree of virulence was generally similar in strains belonging to the same genomovar. Strains of Burkholderia multivorans and some strains of Burkholderia stabilis did not cause symptoms of disease in alfalfa seedlings. Representative strains were also tested for virulence using the rat agar bead model. Most of the strains tested were able to establish chronic lung infections; B. stabilis strains were the exception. Most of the strains that were virulent in the alfalfa infection model were also virulent in the lung infection model. The B. cepacia genomovar III mutants K56pvdA::tp and K56-H15 were significantly less virulent in the alfalfa infection model than their parent strain. Therefore, this alfalfa infection model may be a useful tool for assessing virulence of strains of the B. cepacia complex and identifying new virulence-associated genes.

scholarly journals MCMV Centrifugal Enhancement: A New Spin on an Old Topic

Pathogens ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1577
Author(s):  
Trevor J. Hancock ◽  
Morgan Lynn Hetzel ◽  
Andrea Ramirez ◽  
Tim E. Sparer
Keyword(s):  
Tissue Culture ◽  
Salivary Gland ◽  
Vaccine Development ◽  
Submicron Particles ◽  
Murine Cytomegalovirus ◽  
Submicron Particle ◽  
Congenital Infections ◽  
Life Threatening

Human cytomegalovirus (HCMV) is a ubiquitous pathogen infecting a majority of people worldwide, with diseases ranging from mild to life-threatening. Its clinical relevance in immunocompromised people and congenital infections have made treatment and vaccine development a top priority. Because of cytomegaloviruses’ species specificity, murine cytomegalovirus (MCMV) models have historically informed and advanced translational CMV therapies. Using the phenomenon of centrifugal enhancement, we explored differences between MCMVs derived in vitro and in vivo. We found centrifugal enhancement on tissue culture-derived virus (TCV) was ~3× greater compared with salivary gland derived virus (SGV). Using novel “flow virometry”, we found that TCV contained a distinct submicron particle composition compared to SGV. Using an inhibitor of exosome production, we show these submicron particles are not extracellular vesicles that contribute to centrifugal enhancement. We examined how these differences in submicron particles potentially contribute to differing centrifugal enhancement phenotypes, as well as broader in vivo vs. in vitro MCMV differences.

scholarly journals Deep-learning convolutional neural networks with transfer learning accurately classify COVID-19 lung infection on portable chest radiographs

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e10309
Author(s):  
Shreeja Kikkisetti ◽  
Jocelyn Zhu ◽  
Beiyi Shen ◽  
Haifang Li ◽  
Tim Q. Duong
Keyword(s):  
Deep Learning ◽  
Transfer Learning ◽  
Bacterial Pneumonia ◽  
Lung Infection ◽  
Accurate Diagnosis ◽  
Viral Pneumonia ◽  
X Ray ◽  
Portable Chest ◽  
Chest X Ray ◽  
Lung Infections

Portable chest X-ray (pCXR) has become an indispensable tool in the management of Coronavirus Disease 2019 (COVID-19) lung infection. This study employed deep-learning convolutional neural networks to classify COVID-19 lung infections on pCXR from normal and related lung infections to potentially enable more timely and accurate diagnosis. This retrospect study employed deep-learning convolutional neural network (CNN) with transfer learning to classify based on pCXRs COVID-19 pneumonia (N = 455) on pCXR from normal (N = 532), bacterial pneumonia (N = 492), and non-COVID viral pneumonia (N = 552). The data was randomly split into 75% training and 25% testing, randomly. A five-fold cross-validation was used for the testing set separately. Performance was evaluated using receiver-operating curve analysis. Comparison was made with CNN operated on the whole pCXR and segmented lungs. CNN accurately classified COVID-19 pCXR from those of normal, bacterial pneumonia, and non-COVID-19 viral pneumonia patients in a multiclass model. The overall sensitivity, specificity, accuracy, and AUC were 0.79, 0.93, and 0.79, 0.85 respectively (whole pCXR), and were 0.91, 0.93, 0.88, and 0.89 (CXR of segmented lung). The performance was generally better using segmented lungs. Heatmaps showed that CNN accurately localized areas of hazy appearance, ground glass opacity and/or consolidation on the pCXR. Deep-learning convolutional neural network with transfer learning accurately classifies COVID-19 on portable chest X-ray against normal, bacterial pneumonia or non-COVID viral pneumonia. This approach has the potential to help radiologists and frontline physicians by providing more timely and accurate diagnosis.

scholarly journals Murine cytomegalovirus disseminates independently of CX3CR1, CCL2 or its m131/m129 chemokine homologue

2019 ◽  
Vol 100 (12) ◽  
pp. 1695-1700 ◽  
Author(s):  
Helen E. Farrell ◽  
Kimberley Bruce ◽  
Alec J. Redwood ◽  
Philip G. Stevenson
Keyword(s):  
Salivary Gland ◽  
Murine Cytomegalovirus ◽  
Entry Site ◽  
Fractalkine Receptor ◽  
Systemic Spread ◽  
Infected Cells ◽  
Initial Seeding ◽  
Receptor Cx3cr1 ◽  
Patrolling Monocytes

Cytomegaloviruses (CMVs) use myeloid cells to move within their hosts. Murine CMV (MCMV) colonizes the salivary glands for long-term shedding, and reaches them via CD11c+ infected cells. A need to recruit patrolling monocytes for systemic spread has been proposed, based on poor salivary gland infection in fractalkine receptor (CX3CR1)-deficient mice. We found no significant CX3CR1 dependence of salivary gland infection. CCL2 and the viral m131/m129 chemokine homologue were also redundant for acute MCMV spread, arguing against a need for inflammation or infection to recruit additional monocytes to the entry site. M131/m129 promoted salivary gland infection, but only after the initial seeding of infected cells to this site. Our data support the idea that MCMV disseminates by infecting and mobilizing tissue-resident dendritic cells.

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