Strategies to reduce antimicrobials in livestock and aquaculture, and their impact under field conditions: a structured scoping literature review.

Antimicrobial resistance is a pandemic problem, causing substantial health and economic burdens. Antimicrobials are extensively used in livestock and aquaculture, exacerbating this global threat. Fostering the prudent use of antimicrobials will safeguard animal and human health. A lack of knowledge about alternatives to replace antimicrobials, and their effectiveness under field conditions, hampers changes in farming practices. This work aimed to understand the impact of strategies to reduce antimicrobial usage (AMU) in livestock and aquaculture, under field conditions, using a structured scoping literature review. The Extension for Scoping Reviews of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines (PRISMA-ScR) were followed and the Patient, Intervention, Comparison, Outcome, Time and Setting (PICOTS) framework used. Articles were identified from CAB Abstracts, MEDLINE and Scopus. A total of 7505 unique research articles were identified, 926 of which were eligible for full-text assessment; 203 articles were included in data extraction. Given heterogeneity across articles in the way alternatives to antimicrobials or interventions against their usage were described, there was a need to standardize these by grouping them in categories. There were differences in the impacts of the strategies between and within species; this highlights the absence of a 'one-size-fits-all' solution. Nevertheless, some options seem more promising than others, as their impacts were consistently equivalent or positive when compared with animal performance using antimicrobials. This was particularly the case for bioactive protein and peptides, and feed/water management. The outcomes of this work provide data to inform cost-effectiveness assessments of strategies to reduce AMU.

Long-term efficacy and safety of addition of carboplatin with or without veliparib to standard neoadjuvant chemotherapy in triple-negative breast cancer: 4-year follow-up data from BrighTNess, a randomized phase III trial.

BACKGROUND: Primary analyses of the phase III BrighTNess trial showed addition of carboplatin with/without veliparib to neoadjuvant chemotherapy significantly improved pathological complete response (pCR) rates with manageable acute toxicity in patients with triple-negative breast cancer (TNBC). Here, we report 4.5-year follow-up data from the trial. PATIENTS AND METHODS: Women with untreated stage II-III TNBC were randomized (2 : 1 : 1) to paclitaxel (weekly for 12 doses) plus: (i) carboplatin (every 3 weeks for four cycles) plus veliparib (twice daily); (ii) carboplatin plus veliparib placebo; or (iii) carboplatin placebo plus veliparib placebo. All patients then received doxorubicin and cyclophosphamide every 2-3 weeks for four cycles. The primary endpoint was pCR. Secondary endpoints included event-free survival (EFS), overall survival (OS), and safety. Since the co-primary endpoint of increased pCR with carboplatin plus veliparib with paclitaxel versus carboplatin with paclitaxel was not met, secondary analyses are descriptive. RESULTS: Of 634 patients, 316 were randomized to carboplatin plus veliparib with paclitaxel, 160 to carboplatin with paclitaxel, and 158 to paclitaxel. With median follow-up of 4.5 years, the hazard ratio for EFS for carboplatin plus veliparib with paclitaxel versus paclitaxel was 0.63 [95% confidence interval (CI) 0.43-0.92, P = 0.02], but 1.12 (95% CI 0.72-1.72, P = 0.62) for carboplatin plus veliparib with paclitaxel versus carboplatin with paclitaxel. In post hoc analysis, the hazard ratio for EFS was 0.57 (95% CI 0.36-0.91, P = 0.02) for carboplatin with paclitaxel versus paclitaxel. OS did not differ significantly between treatment arms, nor did rates of myelodysplastic syndromes, acute myeloid leukemia, or other secondary malignancies. CONCLUSIONS: Improvement in pCR with the addition of carboplatin was associated with long-term EFS benefit with a manageable safety profile, and without increasing the risk of second malignancies, whereas adding veliparib did not impact EFS. These findings support the addition of carboplatin to weekly paclitaxel followed by doxorubicin and cyclophosphamide neoadjuvant chemotherapy for early-stage TNBC.

Routine antibiotic therapy in dogs increases the detection of antimicrobial-resistant faecal Escherichia coli.

Background: Antimicrobial resistance (AMR) is a critical health problem, with systemic antimicrobial therapy driving development of AMR across the host spectrum. Objectives: This study compares longitudinal carriage, at multiple timepoints, of AMR faecal Escherichia coli in dogs undergoing routine antimicrobial treatment. Methods: Faecal samples (n = 457) from dogs (n = 127) were examined pretreatment, immediately after treatment and 1 month and 3 months post-treatment with one of five antimicrobials. Isolates were tested for susceptibility to a range of antimicrobials using disc diffusion for each treatment group at different timepoints; the presence/absence of corresponding resistance genes was investigated using PCR assays. The impact of treatment group/timepoint and other risk factors on the presence of resistance [MDR, fluoroquinolone resistance, third-generation cephalosporin resistance (3GCR) and ESBL and AmpC production] was investigated using multilevel modelling. Samples with at least one AMR E. coli from selective/non-selective agar were classed as positive. Resistance was also assessed at the isolate level, determining the abundance of AMR from non-selective culture. Results: Treatment with ß-lactams or fluoroquinolones was significantly associated with the detection of 3GCR, AmpC-producing, MDR and/or fluoroquinolone-resistant E. coli, but not ESBL-producing E. coli, immediately after treatment. However, 1 month post-treatment, only amoxicillin/clavulanate was significantly associated with the detection of 3GCR; there was no significant difference at 3 months post-treatment for any antimicrobial compared with pretreatment samples. Conclusions: Our findings demonstrated that ß-lactam and fluoroquinolone antibiotic usage is associated with increased detection of important phenotypic and genotypic AMR faecal E. coli following routine therapy in vet-visiting dogs. This has important implications for veterinary and public health in terms of antimicrobial prescribing and biosecurity protocols, and dog waste disposal.

Foodborne and Food-Handler Norovirus Outbreaks: A Systematic Review.

Norovirus (NoV) is the commonest cause of gastrointestinal disease in the United Kingdom and in many developed countries, causing diarrhea and vomiting in millions of cases worldwide annually. Transmission is most often mediated from person to person. NoV infection has, however, additionally been associated with the consumption of food, either through the consumption of food contaminated at source such as seafood, berries, and salad, or as a consequence of the foodstuff being contaminated in some way by a food handler during processing or serving. A systematic review of outbreaks attributed to NoV between January 2003 and July 2017 was conducted to assess the contribution of food handlers to the burden of NoV, and to identify foods commonly associated with NoV outbreaks. A total of 3021 articles were screened, of which 27 met the definition of confirmed foodborne outbreaks and 47 met the criteria for definite food-handler NoV outbreaks. Of all food types, shellfish were implicated in the greatest number of definite foodborne outbreaks. Food handlers contributed to definite food-handler outbreaks involving a diverse range of foodstuffs and in a wide variety of settings, including weddings and military establishments. More genotypes of NoV were found in people who were ill than in samples from food and food handlers. The potential for both food products and food handlers to contribute to the burden of NoV infection is demonstrated conclusively.

Impact of systemic antimicrobial therapy on mucosal staphylococci in a population of dogs in Northwest England.

BACKGROUND: Antimicrobial-resistant bacteria are increasingly isolated from veterinary patients. OBJECTIVES: To determine risk factors for antimicrobial resistance (AMR) among canine mucosal staphylococci following routine antimicrobial treatment with cefalexin (CFX), clavulanate-amoxicillin (AC), cefovecin (CVN), clindamycin (CD) or a fluoroquinolone (FQ). ANIMALS: Mucosal swab samples (n = 463) were collected from 127 dogs pre-treatment, immediately, and at one- and three-months post-treatment. METHODS: Staphylococci were identified phenotypically and biochemically as coagulase negative (CoNS) or coagulase positive (CoPS); CoPS were speciated by nuc gene PCR. Antimicrobial susceptibility was determined using disc diffusion and mecA gene carriage by PCR. Multilevel, multivariable models examined associations between risk factors and presence/absence of CoPS, meticillin resistance (MR), multidrug-resistance (MDR) and fluoroquinolone resistance (FQR). RESULTS: The percentage of samples with CoNS increased and with CoPS (including S. pseudintermedius) decreased immediately post-treatment with CFX, CVN and CD (P ≤ 0.001) and one month post-treatment with CD (P = 0.003). By three months post-treatment, there was no significant difference compared to pre-treatment samples. Immediately post-treatment with FQs there was significantly increased risk of isolating MRS (P = 0.002), MDR (P = 0.002) or FQR (P = 0.013) staphylococci and of MDR following CFX treatment (P = 0.019). The percentage of samples with AMR staphylococci declined from immediately to three months post-treatment and there was no significant difference between resistance prevalence at one or three months post-treatment for most AMR traits and treatment groups. Exceptions include increased MDR following FQ (P = 0.048) or CFX (P = 0.021), at one and three months post-treatment, respectively. CONCLUSIONS AND CLINICAL IMPORTANCE: Systemic antimicrobials impact on mucosal staphylococci. Immediately after therapy, the mucosa may be a reservoir for AMR staphylococci that are a source of mobile genetic elements carrying AMR genes.

Are cattle dangerous to walkers? A scoping review.

Anecdotal evidence suggests that people coming into contact with cattle while participating in outdoor pursuits can sustain severe, even fatal injuries. This has negative implications for farmers, cattle and the public. This study outlines findings from a review of published literature, UK media reports and internet guidelines currently available to the UK public for walking near cattle. A total of 54 cattle attacks were reported in the UK media from 1 January 1993 to 31 May 2013; approximately one-quarter resulted in fatality and two-thirds involved dogs. Walking with dogs among cows, particularly with calves present, was a problematic context. Twenty pieces of commonly occurring advice were found within various guidelines. However, there are no definitive approved guidelines, no published studies describing the prevalence of cattle attacks on members of the public and no system in place to document them. Attacks by cattle are underinvestigated and further work should assess their public health impact.

The need for One Health systems-thinking approaches to understand multiscale dissemination of antimicrobial resistance.

Although the effects of antimicrobial resistance (AMR) are most obvious at clinical treatment failure, AMR evolution, transmission, and dispersal happen largely in environmental settings, for example within farms, waterways, livestock, and wildlife. We argue that systems-thinking, One Health approaches are crucial for tackling AMR, by understanding and predicting how anthropogenic activities interact within environmental subsystems, to drive AMR emergence and transmission. Innovative computational methods integrating big data streams (eg, from clinical, agricultural, and environmental monitoring) will accelerate our understanding of AMR, supporting decision making. There are challenges to accessing, integrating, synthesising, and interpreting such complex, multidimensional, heterogeneous datasets, including the lack of specific metrics to quantify anthropogenic AMR. Moreover, data confidentiality, geopolitical and cultural variation, surveillance gaps, and science funding cause biases, uncertainty, and gaps in AMR data and metadata. Combining systems-thinking with modelling will allow exploration, scaling-up, and extrapolation of existing data. This combination will provide vital understanding of the dynamic movement and transmission of AMR within and among environmental subsystems, and its effects across the greater system. Consequently, strategies for slowing down AMR dissemination can be modelled and compared for efficacy and cost-effectiveness.

Rationalising development of classification systems describing livestock production systems for disease burden analysis within the Global Burden of Animal Diseases programme.

The heterogeneity that exists across the global spectrum of livestock production means that livestock productivity, efficiency, health expenditure and health outcomes vary across production systems. To ensure that burden of disease estimates are specific to the represented livestock population and people reliant upon them, livestock populations need to be systematically classified into different types of production system, reflective of the heterogeneity across production systems. This paper explores the data currently available of livestock production system classifications and animal health through a scoping review as a foundation for the development of a framework that facilitates more specific estimates of livestock disease burdens. A top-down framework to classification is outlined based on a systematic review of existing classification methods and provides a basis for simple grouping of livestock at global scale. The proposed top-down classification framework, which is dominated by commodity focus of production along with intensity of resource use, may have less relevance at the sub-national level in some jurisdictions and will need to be informed and adapted with information on how countries themselves categorize livestock and their production systems. The findings in this study provide a foundation for analysing animal health burdens across a broad level of production systems. The developed framework will fill a major gap in how livestock production and health are currently approached and analysed.

Internet cognitive behavioural therapy for mixed anxiety and depression: a randomized controlled trial and evidence of effectiveness in primary care.

BACKGROUND: Major depressive disorder (MDD) and generalized anxiety disorder (GAD) have the highest co-morbidity rates within the internalizing disorders cluster, yet no Internet-based cognitive behavioural therapy (iCBT) programme exists for their combined treatment. METHOD: We designed a six-lesson therapist-assisted iCBT programme for mixed anxiety and depression. Study 1 was a randomized controlled trial (RCT) comparing the iCBT programme (n = 46) versus wait-list control (WLC; n = 53) for patients diagnosed by structured clinical interview with MDD, GAD or co-morbid GAD/MDD. Primary outcome measures were the Patient Health Questionnaire nine-item scale (depression), Generalized Anxiety Disorder seven-item scale (generalized anxiety), Kessler 10-item Psychological Distress scale (distress) and 12-item World Health Organization Disability Assessment Schedule II (disability). The iCBT group was followed up at 3 months post-treatment. In study 2, we investigated the adherence to, and efficacy of the same programme in a primary care setting, where patients (n = 136) completed the programme under the supervision of primary care clinicians. RESULTS: The RCT showed that the iCBT programme was more effective than WLC, with large within- and between-groups effect sizes found (>0.8). Adherence was also high (89%), and gains were maintained at 3-month follow-up. In study 2 in primary care, adherence to the iCBT programme was low (41%), yet effect sizes were large (>0.8). Of the non-completers, 30% experienced benefit. CONCLUSIONS: Together, the results show that iCBT is effective and adherence is high in research settings, but there is a problem of adherence when translated into the 'real world'. Future efforts need to be placed on developing improved adherence to iCBT in primary care settings.

Subacute ruminal acidosis and total mixed ration preference in lactating dairy cows.

Subacute ruminal acidosis (SARA) is a condition where the pH of the rumen becomes abnormally acidic because of increased and altered production of volatile fatty acids. The objective of this experiment was to determine how a SARA challenge affects total mixed ration selection in dairy cows. In this study, 8 multiparous, lactating, ruminally cannulated Holstein cows were given a choice between a long-forage-particle-size diet with slow-fermenting starch (LC) and a short-forage-particle-size diet with fast-fermenting starch in a crossover design. Cows were allowed to adapt to this feeding scheme and were then subjected to a rumen challenge to induce a bout of SARA. The rumen challenge successfully decreased rumen pH and altered rumen volatile fatty acid profiles. Daily average rumen pH decreased from 6.02 to 5.77, and average minimum rumen pH decreased from 5.59 to 5.28. In addition, following the rumen challenge, concentrations of acetate, butyrate, and valerate, and acetate-to-propionate ratio increased. In response to the rumen challenge, intake of LC increased from the baseline level of 18.1% of total daily dry matter intake to 38.3% for that day. During the first recovery day after the rumen challenge, LC intake moderated to 28.0% of total daily dry matter intake. On the second recovery day, LC intake returned to baseline levels at 18.6%. These results indicate that cows are able to alter their diet preference for higher physically effective fiber and slower starch fermentability during a bout of SARA and that they can effectively fully recover from this type of SARA within 72 h when appropriate diets are available.

Capacity for One Health research in the Horn of Africa.

Introduction: In low-and-middle-income countries, many people live near livestock. Rural livelihoods need improvement, however livestock-sector growth is a 'wicked' problem, needing careful management and One Health approaches which balance positive aspects of livestock ownership against deleterious impacts. Materials and methods: A Key Informant survey was delivered to higher education and research institute Units in Horn of Africa, to quantify baseline estimates for One Health research, understand characteristics, and risk factors for usage. Principal results: Four-fifths of Units acknowledged some One Health research; however, this was biased towards human-focused dimensions including at the human/animal/environment-interface and human/animal-interface; One Health approaches were also more often reported when all or the animal/environment dimensions were examined. We detected subject-bias impacting environment-focus in research; only research-focused Units had staff with higher environmental science degrees. Our work suggested good national research buy-in, and Units engaging with national policy-makers most often; local policy-makers were least engaged. Four-fifths of Units had laboratories, with two-thirds processing either human or animal samples and half processing both. Funding for equipment purchase, supplies and maintenance, staff training on technical/safety issues was nearly half that previously identified. Major conclusions: The necessity for One Health research approaches is acknowledged, however our results suggest persistent and systemic neglect of the environment in approaches and research staff education, and a lack of integration across government hierarchies during policy-development, potentially driven by international organisation domination. Further, Units lack funding for laboratory equipment purchase/supplies/maintenance, and staff training on technical/safety issues.

Approaches for disease prioritization and decision-making in animal health, 2000-2021: a structured scoping review.

This scoping review identifies and describes the methods used to prioritize diseases for resource allocation across disease control, surveillance, and research and the methods used generally in decision-making on animal health policy. Three electronic databases (Medline/PubMed, Embase, and CAB Abstracts) were searched for articles from 2000 to 2021. Searches identified 6, 395 articles after de-duplication, with an additional 64 articles added manually. A total of 6, 460 articles were imported to online document review management software (sysrev.com) for screening. Based on inclusion and exclusion criteria, 532 articles passed the first screening, and after a second round of screening, 336 articles were recommended for full review. A total of 40 articles were removed after data extraction. Another 11 articles were added, having been obtained from cross-citations of already identified articles, providing a total of 307 articles to be considered in the scoping review. The results show that the main methods used for disease prioritization were based on economic analysis, multi-criteria evaluation, risk assessment, simple ranking, spatial risk mapping, and simulation modeling. Disease prioritization was performed to aid in decision-making related to various categories: (1) disease control, prevention, or eradication strategies, (2) general organizational strategy, (3) identification of high-risk areas or populations, (4) assessment of risk of disease introduction or occurrence, (5) disease surveillance, and (6) research priority setting. Of the articles included in data extraction, 50.5% had a national focus, 12.3% were local, 11.9% were regional, 6.5% were sub-national, and 3.9% were global. In 15.2% of the articles, the geographic focus was not specified. The scoping review revealed the lack of comprehensive, integrated, and mutually compatible approaches to disease prioritization and decision support tools for animal health. We recommend that future studies should focus on creating comprehensive and harmonized frameworks describing methods for disease prioritization and decision-making tools in animal health.

Livestock health and disease economics: a scoping review of selected literature.

Animal diseases in production and subsistence environments have the potential to negatively affect consumers, producers, and economies as a whole. A growing global demand for animal sourced food requires safe and efficient production systems. Understanding the burden of animal disease and the distribution of burden throughout a value chain informs policy that promotes safe consumption and efficient markets, as well as providing more effective pathways for investment. This paper surveys existing knowledge on the burden of animal disease across economic categories of production, prevention and treatment, animal welfare, and trade and regulation. Our scoping review covers 192 papers across peer-reviewed journals and reports published by organizations. We find there exists a gap in knowledge in evaluating what the global burdens of animal diseases are and how these burdens are distributed in value chains. We also point to a need for creating an analytical framework based on established methods that guides future evaluation of animal disease burden, which will provide improved access to information on animal health impacts.

Approximating the global economic (market) value of farmed animals.

Understanding the global economic importance of farmed animals to society is essential as a baseline for decision making about future food systems. We estimated the annual global economic (market) value of live animals and primary production outputs, e.g., meat, eggs, milk, from terrestrial and aquatic farmed animal systems. The results suggest that the total global market value of farmed animals ranges between 1.61 and 3.3 trillion USD (2018) and is expected to be similar in absolute terms to the market value of crop outputs (2.57 trillion USD). The cattle sector dominates the market value of farmed animals. The study highlights the need to consider other values of farmed animals to society, e.g., finance/insurance value and cultural value, in decisions about the sector's future.

Societal Impacts of Pandemics: Comparing COVID-19 With History to Focus Our Response.

COVID-19 has disrupted everyday life worldwide and is the first disease event since the 1918 H1N1 Spanish influenza (flu) pandemic to demand an urgent global healthcare response. There has been much debate on whether the damage of COVID-19 is due predominantly to the pathogen itself or our response to it. We compare SARS-CoV-2 against three other major pandemics (1347 Black Death, 1520's new world smallpox outbreaks, and 1918 Spanish Flu pandemic) over the course of 700 years to unearth similarities and differences in pathogen, social and medical context, human response and behavior, and long-term social and economic impact that should be used to shape COVID-19 decision-making. We conclude that <100 years ago, pandemic disease events were still largely uncontrolled and unexplained. The extensive damage wreaked by historical pandemics on health, economy, and society was a function of pathogen characteristics and lack of public health resources. Though there remain many similarities in patterns of disease spread and response from 1300 onwards, the major risks posed by COVID-19 arise not from the pathogen, but from indirect effects of control measures on health and core societal activities. Our understanding of the epidemiology and effective treatment of this virus has rapidly improved and attention is shifting toward the identification of long-term control strategies that balance consideration of health in at risk populations, societal behavior, and economic impact. Policymakers should use lessons from previous pandemics to develop appropriate risk assessments and control plans for now-endemic COVID-19, and for future pandemics.

Use of routine death and illness surveillance data to provide insight for UK pandemic planning: lessons from COVID-19.

OBJECTIVES: Reporting of COVID-19 cases, deaths and testing has often lacked context for appropriate assessment of disease burden within risk groups. The research considers how routine surveillance data might provide initial insights and identify risk factors, setting COVID-19 deaths early in the pandemic into context. This will facilitate the understanding of wider consequences of a pandemic from the earliest stage, reducing fear, aiding in accurately assessing disease burden and ensuring appropriate disease mitigation. SETTING: UK, 2020. PARTICIPANTS: The study is a secondary analysis of routine, public domain, surveillance data and information from Office for National Statistics (ONS), National Health Service (NHS) 111 and Public Health England (PHE) on deaths and disease. PRIMARY AND SECONDARY OUTCOME MEASURES: Our principal focus is ONS data on deaths mentioning COVID-19 on the death certificate. We also consider information provided in NHS 111 and PHE data summaries. RESULTS: Deaths with COVID-19 significantly contributed to, yet do not entirely explain, abnormally elevated all-cause mortality in the UK from weeks 12-18 of 2020. Early in the UK epidemic, COVID-19 was the greatest threat to those with underlying illness, rarely endangering people aged under 40 years. COVID-19-related death rates differed by region, possibly reflecting underlying population structure. Risk of COVID-19-related death was greater for healthcare and social care staff and black, Asian and minority ethnic individuals, having allowed for documented risk factors. CONCLUSION: Early contextualisation of public health data is critical to recognising who gets sick, when and why. Understanding at-risk groups facilitates a targeted response considering indirect consequences of society's reaction to a pandemic alongside disease-related impacts. COVID-19-related deaths mainly mirror historical patterns, and excess non-COVID-19-related deaths partly reflect reduced access to and uptake of healthcare during lockdown. Future outbreak response will improve through better understanding of connectivity between disease monitoring systems to aid interpretation of disease risk patterns, facilitating nuanced mitigation measures.

One hundred years of zoonoses research in the Horn of Africa: A scoping review.

BACKGROUND: One Health is particularly relevant to the Horn of Africa where many people's livelihoods are highly dependent on livestock and their shared environment. In this context, zoonoses may have a dramatic impact on both human and animal health, but also on country economies. This scoping review aimed to characterise and evaluate the nature of zoonotic disease research in the Horn region. Specifically, it addressed the following questions: (i) what specific zoonotic diseases have been prioritised for research, (ii) what data have been reported (human, animal or environment), (iii) what methods have been applied, and (iv) who has been doing the research? METHODOLOGY/PRINCIPAL FINDINGS: We used keyword combinations to search online databases for peer-reviewed papers and theses. Screening and data extraction (disease, country, domain and method) was performed using DistillerSR. A total of 2055 studies focusing on seven countries and over 60 zoonoses were included. Brucellosis attracted the highest attention in terms of research while anthrax, Q fever and leptospirosis have been comparatively under-studied. Research efforts did not always align with zoonoses priorities identified at national levels. Despite zoonoses being a clear target for 'One Health' research, a very limited proportion of studies report data on the three domains of human, animal and environment. Descriptive and observational epidemiological studies were dominant and only a low proportion of publications were multidisciplinary. Finally, we found that a minority of international collaborations were between Global South countries with a high proportion of authors having affiliations from outside the Horn of Africa. CONCLUSIONS/SIGNIFICANCE: There is a growing interest in zoonoses research in the Horn of Africa. Recommendations arising from this scoping review include: (i) ensuring zoonoses research aligns with national and global research agendas; (ii) encouraging researchers to adopt a holistic, transdisciplinary One Health approach following high quality reporting standards (COHERE, PRISMA, etc.); and (iii) empowering local researchers supported by regional and international partnerships to engage in zoonoses research.

Accumulation of natural killer and cytotoxic T large granular lymphocytes in the liver during virus infection.

The immunologic mechanisms involved in virus-induced hepatitis were examined by measuring the cytotoxic capabilities and the morphologic and antigenic phenotypes of leukocytes isolated from livers of virus-infected mice. Large granular lymphocytes (LGL) of both natural killer (NK) cell and cytotoxic T lymphocyte (CTL) phenotypes were found to accumulate in livers of mice infected with either the nonhepatotropic Armstrong strain of lymphocytic choriomeningitis virus (LCMV-ARM) or the hepatotropic WE strain (LCMV-WE). Between days 1 and 5 postinfection (p.i.), both viruses induced a three- to fourfold increase in NK cell lytic activity in the livers of C3H/St mice and a three- to fourfold increase in the number of LGL in the organ. These LGL were characterized as NK cells on the basis of cell surface antigens, kinetics of appearance, target cell range, and morphology. By day 7 p.i., virus-specific, H-2-restricted, Thy-1+, Lyt-2+, CTL activity was present in the liver, and its appearance correlated with a second wave of LGL accumulation. CTL activity, total leukocyte number, and CTL/LGL number were at least fivefold higher in the livers of mice infected with LCMV-WE than with LCMV-ARM. The dramatic LCMV-WE-induced day 7 increases in total leukocytes and LGL were absent in athymic nude (nu/nu) mice, suggesting that the increases were T cell-dependent. LCMV-ARM infection of C57BL/6 mice induced significant spleen CTL activity but little liver CTL activity, whereas LCMV-WE infection resulted in significant liver CTL activity but minimal spleen CTL activity. Mice infected with the cytopathic hepatotropic viruses, mouse hepatitis virus (MHV) and murine cytomegalovirus (MCMV), experienced much greater increases in liver NK/LGL by day 3 p.i. than did mice infected with LCMV or injected with the interferon-inducer poly(I-C). MHV-infected mice homozygous for the beige (bg/bg) mutation also exhibited significant increases in liver NK/LGL cell number and activity, although the activity was less than heterozygote controls, and the morphology of the LGL granules was aberrant. These data show that the LGL accumulate in virus-infected organs, in this case, the liver. An early NK/LGL influx is most pronounced during infection with cytopathic hepatotropic viruses. This initial influx of NK/LGL is followed later by an influx of CTL also possessing LGL morphology. The CTL/LGL response in the liver is significantly greater during hepatotropic virus infections, even when a strong CTL response in the spleen is lacking.

Interleukin 1: an important mediator of host resistance against Pneumocystis carinii.

The importance of endogenous interleukin 1 (IL-1) in resistance to Pneumocystis carinii infection was examined in a SCID mouse model. Naturally acquired pulmonary infection of P. carinii in SCID mice was completely cleared by reconstitution of the infected mice with immunocompetent spleen cells. IL-1 activity in the lung homogenate supernatant of these mice increased significantly after reconstitution and returned to baseline level after the clearance of P. carinii. Treatment of reconstituted SCID mice with 35F5, a monoclonal antibody against murine type I IL-1R almost completely inhibited the clearance of P. carinii. In contrast, treatment with control rat immunoglobulin G had no detectable effect. Further study revealed that for the complete clearance of P. carinii, IL-1 must be present at the early stage of immune responses induced by reconstitution, since clearance could be blocked by a single injection of 35F5 into SCID mice at 2 d, but not at either 8 or 13 d postreconstitution. Furthermore, pulmonary recruitment of neutrophils, macrophages, and lymphocytes was significantly inhibited in mice that received 35F5 treatment. These findings strongly suggest that, in reconstituted SCID mice, endogenous IL-1 is important in host resistance to P. carinii infection and that IL-1 may function early in the host response possibly by the recruitment of inflammatory cells into the lungs.