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PubMed1979

An epidemiologic approach to host factors in the etiology of cancer.

We examined the contribution of host factors in carcinogenesis by evaluating the frequency distributions and secular trends in available epidemiologic data of mortality and morbidity around the world. In most developed countries, the age-adjusted death rates of cancer of all sites have levelled off in recent years and the intercountry difference in mortality is small. Deaths from cancer account for approximately 20% of total deaths in these countries. It is believed that the difference in cancer mortality of all sites between the developed and developing countries can be explained by the different levels of mortality from infectious and parasitic diseases, including deaths from tuberculosis. A certain upper limit for the number of cancer deaths in each population is strongly suggested by the unaltered cumulative mortality rate from cancer and tuberculosis up to 85 years of age in a defined birth cohort in the developed countries. The apparent age dependency in cancer mortality as well as some other essential epidemiologic implications in carcinogenesis, the commonly observed proportion of cancer deaths of around 20% of total deaths, and the well-known etiologic importance of environmental factors which determines the site-specific cancer mortality and morbidity lead one to consider the definite existence of "susceptibles to cancer" in each population. However, the concept of susceptibles to cancer is different from the usual one of hereditary predisposition to so-called "intractable diseases," which have low incidence rates.

Adolescent↗

PubMed1976

Host factors in chronic obstructive pulmonary disease in an upper Midwest rural community. Design, case selection, and clinical characteristics in a matched-pair study.

A series of 111 index subjects with chronic obstructive pulmonary disease (COPD) who had forced expiratory volume in 1 second (FEV1) of 70% or less of that predicted were matched on the basis of age, sex, occupation, and smoking history with control subjects who had an FEV1 of 85% or more of that predicted. Index and control subjects with seasonal or reversible airway disease were excluded. Men outnumbered women by a ratio of 4.5 to 1. Thirty-five percent of the women and 2% of the men were nonsmokers (0 pack-years). There were three PiZ phenotypes in the index group (two nonsmokers) and none in the controls. PiMZ phenotypes in the index group outnumbered those in the controls by 8 to 5. Host factors that might be important in these closely matched pairs were sought by history, physical examination, and a large battery of laboratory tests. A standard respiratory questionnaire revealed the anticipated significantly higher frequency of cough, phlegm, noisy respiration, and all grades of dyspnea in index subjects. Previous lower respiratory tract infections also were more frequent in index subjects than in controls. There were no detectable differences between groups in the frequency of upper airway infections, nasal polyps, sinus surgery, or reported allergy to any substance. If the British Medical Research Council's definition of chronic bronchitis were applied to our study, about two-thirds of our index subjects and almost one-third of our controls would be considered to have chronic bronchitis. Pack-years of smoking were not significantly associated with the amount and duration of cough and expectoration in male or female index subjects or controls. Significant differences between index and control groups on physical examination included the audible forced expiratory flow time over the trachea, the estimated maximal midexpiratory flow, breath sounds, rales, and total excursion of the hemidiaphragms. An endocrine questionnaire and measurement of blood sex hormones did not give any clues as to the propensity of males to develop COPD. Women with airway obstruction similar to that of men had histories of significantly fewer pack-years than did the men, and there was a much larger proportion of women who never smoked. Further studies, specifically on genetic and immunologic characteristics, are under way to identify potential host factors.

Bronchitis↗

PubMed2025

Global siRNA screen identifies human host factors critical for SARS-CoV-2 replication and late stages of infection.

Defining the subset of cellular factors governing SARS-CoV-2 replication can provide critical insights into viral pathogenesis and identify targets for host-directed antiviral therapies. While a number of genetic screens have previously reported SARS-CoV-2 host dependency factors, most of these approaches relied on utilizing pooled genome-scale CRISPR libraries, which are biased toward the discovery of host proteins impacting early stages of viral replication. To identify host factors involved throughout the SARS-CoV-2 infectious cycle, we conducted an arrayed genome-scale siRNA screen. Resulting data were integrated with published functional screens and proteomics data to reveal (i) common pathways that were identified in all OMICs datasets-including regulation of Wnt signaling and gap junctions, (ii) pathways uniquely identified in this screen-including NADH oxidation, or (iii) pathways supported by this screen and proteomics data but not published functional screens-including arachionate production and MAPK signaling. The identified proviral host factors were mapped into the SARS-CoV-2 infectious cycle, including 32 proteins that were determined to impact viral replication and 27 impacting late stages of infection, respectively. Additionally, a subset of proteins was tested across other coronaviruses revealing a subset of proviral factors that were conserved across pandemic SARS-CoV-2, epidemic SARS-CoV-1 and MERS-CoV, and the seasonal coronavirus OC43-CoV. Further studies illuminated a role for the heparan sulfate proteoglycan perlecan in SARS-CoV-2 viral entry and found that inhibition of the non-canonical NF-kB pathway through targeting of BIRC2 restricts SARS-CoV-2 replication both in vitro and in vivo. These studies provide critical insight into the landscape of virus-host interactions driving SARS-CoV-2 replication as well as valuable targets for host-directed antivirals.

Humans↗

PubMed1992

Escherichia coli integration host factor stabilizes bacteriophage Mu repressor interactions with operator DNA in vitro.

Using gel retardation and DNase I protection techniques, we have demonstrated that the Escherichia coli integration host factor (IHF) stabilizes the interaction between Mu repressor and its cognate operator-binding sites in vitro. These results are discussed in terms of a model in which IHF may commit the phage to the lytic or lysogenic pathway depending on the occupancy of the operator sites by the repressor.

Bacterial Proteins↗

PubMed1976

Rat polyvinyl sponge model for the study of infections: host factors and microbial proliferation.

Female rats were treated with several administration regimens of methylprednisolone, cobra venom anti-complementary factor, and cyclophosphamide in conjunction with polyvinyl sponge implantations. The effect of these drugs on host factors active against bacteria was evaluated with Staphylococcus aureus ATCC 25933, Escherichia coli K-12, and Pseudomonas aeruginosa CDC 7725. One of two implants in each animal was infected with 10(8) of one of the three bacteria, and bacterial and granulocyte content was determined in the infected and control sponges after 48 h. The single large dose of methylprednisolone decreased staphylococcal and E. coli clearance while promoting dissemination of P. aeruginosa. A low chronic dose of the steroid inhibited E. coli chemotaxis only. A higher dose of the steroid administered chronically interfered markedly with S. aureus and E. coli curtailment by the host while leading to enhanced dissemination of P. aeruginosa, accompanied by a precipitous decline in granulocytes. Results with cobra factor resembled the higher chronic dose of steroid enhancing, especially the dissemination of the pseudomonad and its anti-granulocytic propensity. Cyclophosphamide depression of granulocytes revealed the rat's ability to curtail the proliferation of particular S. aureus and E.coli strains even in the absence of leukocytes. This treatment resulted in the rapid spread of P. aeruginosa, leading to the death of some experimental animals. These experiments underline the versatility of this animal model in the study of host and microbial factors influential in infectious disease.

Animals↗

PubMed1977

Host factor for coliphage Qbeta RNA replication as an aid in elucidating phylogenetic relationships: the genus Pseudomonas.

Host Factor (HF) is a heat-stable RNA-binding protein required along with Qbeta replicase for in vitro transcription of coliphage Qbeta RNA. We have found that HF activity and antigenicity are conserved among certain Gram-negative bacterial species. We examined selected species within the genus Pseudomonas for the presence of the HF polypeptide's antigenicity and Qbeta RNA replication function. While we were unable to detect either of these in Pseudomonas diminuta or Pseudomonas vesicularis, the other eleven species tested contained cross-reacting material to Escherichia coli HF. Furthermore, in six of these eleven species we were able to detect HF activity. The detection of HF structure and function allowed the examined species to be grouped into three categories which we have called 'sets'. The results correlate well with those of previous studies on ribosomal RNA homology (Palleroni et al., 1973).

Antigens, Bacterial↗

PubMed1978

A respiratory survey of cedar mill workers. II. Influence of work-related and host factors on the prevalence of symptoms and pulmonary function abnormalities.

The influence of certain work-related and host factors on the prevalence of respiratory symptoms and pulmonary function abnormalities in 405 red cedar workers and 187 control workers was examined. In cedar workers, but not in controls, the prevalence of chest symptoms increased with duration of exposure. The decline in pulmonary function with increasing duration of exposure was also more marked in cedar workers, but in both groups smoking was a more important determinant. Substantial proportions of cedar workers and, to a lesser extent, controls noted improvement of cough and wheeze, and particularly of conjunctivitis and rhinitis, when away from work. No deterioration, however, was found in pulmonary function during the work week in either exposure group. Atopic status was unrelated to the prevalence of chest symptoms or pulmonary function abnormalities; it was more common in workers with conjunctivitis and rhinitis, particularly in the cedar group. Similarly, Pi phenotype did not appear to influence the occurrence of either symptoms or lung function abnormalities.

Adult↗

PubMed1992

Catabolite gene activator protein and integration host factor act in concert to regulate tdc operon expression in Escherichia coli.

Anaerobic expression of the tdcABC operon of Escherichia coli requires cyclic AMP and the catabolite gene activator protein (CAP). Purified CAP binds to a 30-bp sequence in the tdc promoter between positions -55 and -26, and a mutant CAP site with base substitutions at positions -48, -47, and -45 failed to bind CAP and also drastically reduced the beta-galactosidase expression from a tdcB'-'lacZ fusion plasmid. Recently, we showed that efficient expression of the tdc operon also requires a functional integration host factor (IHF) and an IHF-binding site in the tdc promoter between positions -118 and -88. The levels of beta-galactosidase activity from the tdcB'-'lacZ fusion plasmids were also reduced in an IHF-deficient strain with the wild-type or mutant plasmid CAP sequence. In vitro footprinting experiments revealed that CAP and IHF occupy their specific binding sites on tdc DNA when they are present separately or together. These regulatory proteins also induced significant bending of the tdc promoter DNA. Our results suggest that CAP and IHF act in concert as positive transcription factors for tdc operon expression in vivo.

Anaerobiosis↗

PubMed1976

Host factor requirements and some properties of phiXtB. An evolutionary aspect of phiX-type phages.

Replication of phiXtB, a capsid mutant of bacteriophage phiX174, depends on the host functions directed by the E.coli genes dnaE, dnaF, dnaG, dnaZ, lig and rep. The cellular products of dnaA, dnaB, dnaC(D), dnaI, dnaP, polA, polB and xth genes are, however, dispensable for the viral growth. In these host factor requirements, phiXtB resembles phages phiK and St-1 rather than phiX174. Host ranges of phiXtB, St-1 and phiK overlap considerably, and growth temperature of the three phages is somewhat higher than that of phiX174. Furthermore, phiXtB is, like phiK, inactivated by antiserum against St-1. phiXtB may thus fill an evolutionary gap between the phiX174 group and the St-1 group.

Biological Evolution↗

PubMed1992

Role of integration host factor in stimulating transcription from the sigma 54-dependent nifH promoter.

In a wide variety of nitrogen-fixing organisms among the Purple Bacteria (large division of Gram-negative bacteria) the nitrogen fixation (nif) operons are transcribed by an alternative holoenzyme form of RNA polymerase, sigma 54-holoenzyme. Transcription depends on the activator protein NIFA (nitrogen fixation protein A), which catalyzes isomerization of closed complexes between this polymerase and a promoter to transcriptionally productive open complexes. NIFA-mediated activation of transcription from the nifH promoter of Klebsiella pneumoniae is greatly stimulated by the integration host factor IHF, which binds to a site between the upstream binding site for NIFA and the promoter, and bends the DNA. IHF fails to stimulate activation of transcription from this promoter by another activator of sigma 54-holoenzyme, NTRC (nitrogen regulatory protein C), which lacks a specific binding site in the nifH promoter region. As predicted, if the IHF-induced bend facilitates interaction between NIFA and sigma 54-holoenzyme, substitution of an NTRC-binding site for the NIFA-binding site allowed IHF to stimulate NTRC-mediated activation of transcription from the nifH promoter. The stimulation was of the same order of magnitude as that for NIFA in the native configuration of the promoter-regulatory region (up to 20-fold). With purified NTRC and the substitution construct we could demonstrate that stimulation by IHF in a purified transcription system was comparable to that in a crude coupled transcription-translation system, indicating that the stimulation in the crude system could be accounted for by IHF. The IHF stimulation was observed on linear as well as supercoiled templates, indicating that the geometric requirements are relatively simple. We have attempted to visualize the arrangement of proteins on DNA fragments carrying the nifH promoter-regulatory region of K. pneumoniae by electron microscopy. IHF stimulated NIFA-mediated activation of transcription from the nifH and nifD promoters of Bradyrhizobium japonicum and less so from the nifH promoters of Rhizobium meliloti and Thiobacillus ferrooxidans, consistent with previous observations that stimulation is greatest at promoters that are weak binding sites for sigma 54-holoenzyme in closed complexes.

Bacterial Proteins↗

PubMed1976

Role of host factors in the pathogenesis of Salmonella-associated arthritis in rats.

To evaluate the roles of the infectious agent and the host in the pathogensis of Salmonella-associated arthritis (SAA), 1O(3) to 10(6) heat-killed Salmonella enteritidis were injected directly into involved carpal joints in normal and actively immunized rats and in hosts adoptively immunized by the intravenous transfer of spleen cells from syngeneic donors with ongoing SAA. As many as 10(6) living Salmonellae invariably failed to generate more than a transient inflammatory response in normal rats. The regression of acute joint swelling was accelerated in both types of immunized hosts. The intensity and duration of acute inflammation evoked in normal rats by 10(6) and 10(9) heat-killed Salmonellae did not exceed the response elicited by 10(3) living organisms. In sharply contrasting results, however, a chronic arthritis became established in a significant number of actively and adoptively sensitized rats after the intra-articular injection of 10(9) heat-killed organisms. No Salmonellae were recovered from these adoptively sensitized rats although small numbers of organisms has been present among the spleen cells in the transfer inocula. Taken together, these results indicate the obligatory involvement of host factors in the mediation of this chronic arthritis and virtually eliminate any likelihood that joint damage in SAA is due to the directly destructive effects of intra-articular infection.

Animals↗

PubMed1975

Experimental immune arthritis: host factors.

An experimental chronic mono-arthritis was induced in rabbits using adjuvants and bovine serum albumin. The results suggest that unidentified host factors (possibly genetic) influence the induction of delayed hypersensitivity to the antigen. The data further show a clear correlation between systemic cell mediated immunity and chronic synovitis. When this condition is absent, there is a poor correlation between the humoral response and the arthritis. The results make difficult the interpretation of local immune complex deposition as the sole, chronic phlogistic stimulus. (J Rheumatol 2: 373-383, 1975).

Adjuvants, Immunologic↗

PubMed1992

Host factors versus virulence-associated bacterial characteristics in neonatal and infantile bacteraemia and meningitis caused by Escherichia coli.

Possession of P fimbriae, virulence-associated O and K antigens, haemolysin and aerobactin production, and susceptibility to 10 antimicrobial agents were studied in 63 Escherichia coli strains isolated from blood or CSF of infants who were grouped according to their clinical characteristics. These isolates were compared with 35 faecal E. coli strains from healthy infants. Individual virulence factors showed a relatively weak association with invasive infection except for P fimbriae in urosepsis and aerobactin production in meningitis. Combinations of factors were generally more predictive for defining virulent clones, particularly in infants defined as being at normal risk of developing septicaemia. Thus, 62% of isolates from such infants had characteristics typical of previously described uropathogenic or meningitis-associated clones of E. coli, compared with 32% of the isolates from high-risk infants (i.e., those defined as being at high risk of developing septicaemia) and only 9% of the faecal isolates (p less than 0.001 and less than 0.05, respectively). Overall, 45% of the episodes of invasive infection were caused by such clones, whereas risk factors (conditions considered to be associated with increased risk of invasive infection) were present in 59% of the infected infants (39% in meningitis and urosepsis, 78% in cryptogenic septicaemia and untreated bacteraemia). The results indicated that bacterial factors played a significant causative role in neonatal meningitis and urosepsis, particularly in normal-risk infants, whereas predisposing host factors contributed greatly to cryptogenic septicaemia and untreated bacteraemia.

Antigens, Bacterial↗

PubMed2025

Proximity interactome of alphavirus replicase component nsP3 includes proviral host factors eIF4G and AHNAK.

All positive-strand RNA viruses replicate their genomes in association with modified intracellular membranes, inducing either membrane invaginations termed spherules, or double-membrane vesicles. Alphaviruses encode four non-structural proteins nsP1-nsP4, all of which are essential for RNA replication and spherule formation. To understand the host factors associated with the replication complex, we fused the efficient biotin ligase miniTurbo with Semliki Forest virus (SFV) nsP3, which is located on the cytoplasmic surface of the spherules. We characterized the proximal proteome of nsP3 in three cell lines, including cells unable to form stress granules, and identified >300 host proteins constituting the microenvironment of nsP3. These included all the nsPs, as well as several previously characterized nsP3 binding proteins. However, the majority of the identified interactors had no previously identified roles in alphavirus replication, including 39 of the top 50 interacting proteins. The most prominent biological processes involving the proximal proteins were nucleic acid metabolism, translational regulation, cytoskeletal rearrangement and membrane remodeling. siRNA silencing confirmed six novel proviral factors, USP10, AHNAK, eIF4G1, SH3GL1, XAB2 and ANKRD17, which are associated with distinct cellular functions. All of these except SH3GL1 were also important for the replication of chikungunya virus. We discovered that the small molecule 4E1RCat, which inhibits the interaction between the canonical translation initiation factors eIF4G and eIF4E, exhibits antiviral activity against SFV. Since the same molecule was previously found to inhibit coronaviruses, this suggest the possibility that translation initiation factors could be considered as targets for broadly acting antivirals.

Viral Nonstructural Proteins↗

PubMed1992

The sialylation of gonococcal lipopolysaccharide by host factors: a major impact on pathogenicity.

The resistance of gonococci in most patients to complement mediated killing by human serum is due to sialylation of their lipopolysaccharide (LPS) which prevents bactericidal antibody from reacting with target sites. Two of the host factors responsible are: cytidine 5'-monophospho-N-acetyl neuraminic acid (CMP-NANA), a well-known sialylating agent, and another factor which enhances the transfer of sialyl groups from CMP-NANA to LPS catalysed by a gonococcal sialyltransferase. The bacterial determinant of resistance is a conserved LPS component of about 4.5 kDa which is sialylated at a terminal Gal beta 1-4GlcNAc site on its side chain. The sialylated LPS forms a surface coat which is stainable by ruthenium red and connected with previously described 'capsules'. These observations sparked off an explosion of research. Recent publications show that sialylation of LPS by CMP-NANA affects additional important aspects of gonococcal pathogenicity, notably interactions with antibodies and phagocytes, and rendering the gonococcal surface more 'host-like'. Also, the observations have prompted an examination of LPS from some other pathogens for the presence of sialyl groups with positive results for Neisseria meningitidis and Haemophilus influenzae.

Antibodies, Bacterial↗

PubMed1977

Viral attributes and host factors in carcinogenesis: herpesviruses.

This paper describes two different experiments of nature: 1) the persistence of unusual virus strains of Epstein-Barr virus (EBV) (which proved oncogenic in vitro) and cytomegalovirus (CMV) in lymphoid cells following congenital or early acquired infection; 2) the occurence of multiple cases of Burkitt's lymphoma and nasopharyngeal carcinoma in one family. All the members of this family were EBV viral capsid antigen (VCA) and nuclear antigen (EBNA) antibody positive. The two patients with nasopharyngeal carcinoma had high titers of EBV-VCA, EA, and EBNA antibodies. The only member of this family having EBV early antigen (EA antibodies in addition to the patients with tumors was the mother. Borderline IgA deficiency was documented in 3 members of this family. These findings illustrate the importance of host factors (intracellular resistance to transformation and secondarily, immunological surveillance) in the outcome of the host-virus challenge whether cancer or infectious disease is the outcome. Extensive studies of these cases may provide the best insight into the mysteries of viral oncogenesis.

Antibodies, Viral↗

PubMed2025

Viral and host factors associated with SARS-CoV-2 disease severity in Georgia, USA.

While SARS-CoV-2 vaccines have shown strong efficacy, the continued emergence of new viral variants raises concerns about the ongoing and future public health impact of COVID-19, especially in locations with suboptimal vaccination uptake. We investigated viral and host factors, including vaccination status, that were associated with SARS-CoV-2 disease severity in a setting with low vaccination rates. We analyzed clinical and demographic data from 1,957 individuals in the state of Georgia, USA, coupled with viral genome sequencing from 1,185 samples. We found no specific mutations associated with disease severity. Compared to those who were unvaccinated, vaccinated individuals experienced less severe SARS-CoV-2 disease, and the effect was similar for both variants. Vaccination within the prior 3-9 months was associated with decreased odds of moderate disease, severe disease, and death. Older age and underlying health conditions, especially immunosuppression and renal disease, were associated with increased disease severity. Overall, this study provides insights into the impact of vaccination status, variants/mutations, and clinical factors on disease severity in SARS-CoV-2 infection when vaccination rates are low. Understanding these associations will help refine and reinforce messaging around the crucial importance of vaccination in mitigating the severity of SARS-CoV-2 disease.

Humans↗

PubMed1992

Use of host factors to identify people at high risk for cutaneous malignant melanoma .

OBJECTIVE: To determine which host characteristics are risk factors for cutaneous malignant melanoma in order to aim prevention and early detection programs at people at high risk. DESIGN: Case-control study. SETTING: Southern Ontario. SUBJECTS: The 583 case subjects were aged 20 to 69 years and had had malignant melanoma newly diagnosed between Oct. 1, 1984, and Sept. 30, 1986. The 608 control subjects were randomly selected from a list of residents in the study area and were stratum matched for age, sex and municipality. INTERVENTION: Through in-person interviews the interviewer ascertained exposure to putative external risk factors and assessed skin colour and number of nevi on the arm, and the subject reported his or her natural hair colour at age 20 years, eye colour, skin reaction to repeated sun exposure, and freckle and whole-body nevus densities. RESULTS: Although all the host factors mentioned were significantly associated with melanoma risk when considered separately, only hair colour, skin reaction to repeated sun exposure, and self-reported freckle and nevus densities remained significant after backward logistic regression analysis. The odds ratio for melanoma was estimated to be 10.7 in people who had many nevi compared with those who had none (95% confidence interval [CI] 6.6 to 17.4), 4.0 in people who had red hair compared with those who had black hair (95% CI 1.9 to 8.2), 1.9 in people who had many freckles compared with those who had none or few (95% CI 1.3 to 2.8) and 1.4 respectively in people who burned and had a subsequent increase in tan and those who burned and had no increase in tan after repeated sun exposure compared with those who did not burn [corrected]. CONCLUSIONS: Four risk factors for malignant melanoma have been identified. Prospective evaluation of their predictive value should be done. In the meantime, however, these factors should be used to identify people apparently at high risk for malignant melanoma, who can then be targeted for early detection and prevention programs.

Adult↗