Nonspecific Host Response Research Articles

Dalbavancin Boosts the Ability of Neutrophils to Fight Methicillin-Resistant Staphylococcus aureus.

Polymorphonuclear leukocytes (PMNs) are the most important cell type involved in the early nonspecific host response to bacterial pathogens. Staphylococcus aureus has evolved mechanisms to evade immune responses that contribute to its persistence in PMNs, and acquired resistance to several antimicrobials. Additionally, methicillin-resistant S. aureus (MRSA) is one of the most common causes of acute bacterial skin and skin-structure infections (ABSSSIs). Dalbavancin (DBV), a lipoglycopeptide, is indicated for the treatment of ABSSSIs, and has a broad spectrum of action against most microorganisms. Here, we sought to determine the effect of DBV on the neutrophil killing of MRSA and its potential immunomodulating activity. Our results revealed that DBV boosts MRSA killing by acting on both bacteria and PMNs. DBV pre-treatment of PMNs did not change the respiratory burst or degranulation, while an increased trend in neutrophil extracellular traps-associated elastase and in the production of TNFα and CXCL8 was revealed. In parallel, DBV caused a delay in the apoptosis of MRSA-infected neutrophils. In conclusion, we demonstrated a cooperative effect between the antimicrobial properties of PMNs and DBV, thus owing to their immunomodulatory activity. In the choice of the treatment management of serious S. aureus infections, DBV should be considered as an outstanding option since it reinforces PMNs pathogen clearance capability by exerting its effect directly, not only on MRSA but also on neutrophils.

Evaluation of the susceptibility of Prunus rootstock genotypes to Armillaria and Desarmillaria species

Variation in susceptibility of 28 Prunus rootstock genotypes to the causal agents of Armillaria root rot, Armillaria mellea, A. solidipes, and Desarmillaria tabescens, were studied by conducting in vitro root screening assays. Root segments with wounded and intact periderm were placed next to and on the top of the fungal cultures. At day 21, the percent success of fungal penetration and the circumferential and longitudinal lengths of fungal growth were measured. A parallel investigation using the inoculated root segments was carried out to characterize the active host defense mechanisms involved, including anatomical responses in bark and wood. Overall, the success of penetration and the longitudinal and circumferential spread of Armillaria spp. and D. tabescens were significantly different among various Prunus rootstock genotypes. None of the tested rootstock genotypes were completely resistant to infection. However, plum and plum derived rootstocks, and some of the cherry genotypes were less susceptible to infection compared to the peach genotypes. The host’s ability to limit infection by Armillaria spp. and D. tabescens was not limited to a single mechanism but appeared to be regulated by several collective nonspecific host responses acting together. Differential levels of a series of non-specific coordinated events were triggered in Prunus genotypes such as the formation of new callus tissue on the root surface, a colored reaction zone, necrophylactic periderm, new cells, and new vascular cambium to compartmentalize the pathogen. The host responses were elevated in the genotypes with low level of infection as compared to highly infected genotypes.

Mass Spectrometry-Based Quantitative Proteomics of Murine-Derived Polymorphonuclear Neutrophils.

Polymorphonuclear cells (PMNs or neutrophils) are the most abundant leukocyte in humans and represent an essential component of the innate immune system. The ability of neutrophils to initiate an immediate and non-specific host response against invading microbial species is the key to determining the outcome of infection. Neutrophils produce and secrete a plethora of immunomodulatory proteins, including major granule proteins and cytokines, as well as various enzymes, which regulate adherence, phagocytosis, chemotaxis, and cell survival. Historically, characterization of neutrophils and their roles during infection have relied on genetic and phenotypic analyses, as well as biochemical assays. However, recent advances in mass spectrometry-based proteomic workflows and technological platforms have supported the comprehensive profiling of neutrophil-associated immune responses in consideration of cellular factors and secreted proteins. Given the critical role of neutrophils in maintaining and regulating innate immune function, comprehensive profiling of their response to infection is imperative to ensuring host survival. Here, we briefly discuss the role of neutrophils in host-defense and describe methods to purify neutrophils from murine samples and comprehensively profile their proteomes. © 2019 by John Wiley & Sons, Inc.

Zinc Alleviates Lipopolysaccharide Interference with Both Body Temperature and Sickness Behavior in Virgin Female Rats

Objectives: Previous studies from our group showed that lipopolysaccharide (LPS) exposure induces several signs of sickness behavior, including a decrease in food consumption, body weight gain, adipsia, and a biphasic effect in tympanic temperature with a first phase of hypothermia, followed by an increased tympanic temperature. LPS can activate a chain of nonspecific host responses, including the immune response, and decreased zinc levels. In addition, there are differences in the immune response between males and females, particularly fever, with sex hormones interfering with body temperature. This study aims to characterize the effects of zinc treatment on tympanic temperature, body weight gain, food and water consumption, and general activity in open field of virgin female rats exposed to a dose of LPS that was previously reported to induce sickness behavior. Methods: Virgin female Wistar rats were treated with either saline (S) or LPS. One hour later, the S group received another injection of saline (S + S group), half of the LPS group received saline (LPS + S group) and the other half received zinc (LPS + Zn group). Tympanic temperature, body weight, and water and food consumption were measured for 96 h. Measurements and observations started 2 h after LPS administration. Results: Treatment with zinc attenuated LPS-increased temperature, decreased the body weight gain and food consumption, and water consumption was increased. Conclusion: Zinc treatment is beneficial as it reduces the increased tympanic temperature induced by LPS, but it does not influence other sickness behavior caused by exposure to LPS.

Monocyte Response to Different Campylobacter jejuni Lysates Involves Endoplasmic Reticulum Stress and the Lysosomal⁻Mitochondrial Axis: When Cell Death Is Better Than Cell Survival.

Campylobacter jejuni is a Gram-negative spiral-shaped bacterium, commonly associated with gastroenteritis in humans. It explicates its virulence also by the cytolethal distending toxin (CDT), able to cause irreversible cell cycle arrest. Infection by C. jejuni may result in the development of the Guillain–Barré Syndrome, an acute peripheral neuropathy. Symptoms of this disease could be caused by CDT-induced cell death and a subsequent inflammatory response. We tested C. jejuni lysates from different strains on donor monocytes: in fact, monocytes are potent producers of both pro- and anti-inflammatory cytokines, playing a major role in innate immunity and in non-specific host responses. We found, by cytometric and confocal analyses, that mitochondria and lysosomes were differently targeted: The C. jejuni strain that induced the most relevant mitochondrial alterations was the ATCC 33291, confirming an intrinsic apoptotic pathway, whereas the C. jejuni ISS 1 wild-type strain mostly induced lysosomal alterations. Lysates from all strains induced endoplasmic reticulum (ER) stress in monocytes, suggesting that ER stress was not associated with CDT but to other C. jejuni virulence factors. The ER data were consistent with an increase in cytosolic Ca2+ content induced by the lysates. On the contrary, the changes in lysosomal acidic compartments and p53 expression (occurring together from time 0, T0, to 24 h) were mainly due to CDT. The loss of p53 may prevent or impede cell death and it was not observable with the mutant strain. CDT not only was responsible for specific death effects but also seemed to promote an apoptotic stimuli-resisting pathway.

The influence of LPS and zinc on interaction between mother and offspring

IntroductionThe maternal behavior consists of a set of behavioral and physiological changes in adults, performed around the reproductively immature individuals, ensuring their survival and propagation of the species. Offsprings give signal to be collected when separated from their mother through olfactory, visual and sound signals. Infection and its influence in the context of the interaction between mother and offspring is poorly investigated. The classic disease model, which is widely used, involves the treatment with lipopolysaccharide (LPS), the major component of the cell wall of Gram‐negative bacteria. The infections can activate a chain of nonspecific host responses, including the immune response and levels of zinc.ObjectiveTo investigate the behavioral and neuroimmunological adaptations of rats and their offspring resulting from experimental inflammation produced by LPS and the possible influence of zinc treatment on these adaptations.MethodsIn this study, virgin, pregnant and lactating female rats received LPS (100 μg/kg, ip) and then were treated with zinc (2 mg/kg, sc). Temperature, body weight, water and food consumption were measured for ninety‐six hours, starting two hours after LPS administration. On the fifth day of lactation, maternal behavior, the overall activity in the open field and ultrasonic vocalization in offsprings were observed. On the day of weaning, pups of these females received a challenge with LPS (50 μg/kg, ip) and two hours after administration were observed for general activity in the open field. The burst and phagocytosis of leukocytes in the blood of pups was also studied.Results1) in virgin, pregnant and lactating rats, the exposure to LPS and the treatment with zinc modified the temperature, body weight, water and food consumption, and the general activity observed in the open field. Virgin, pregnant or lactating rats responded differently to this treatment. 2) In the lactation period the latency to search the first pup was reduced. 3) In the offspring, a change in the pattern of vocalization of the offspring, changes in general activity observed in the open field and changes in the burst and phagocytosis of leukocytes on the twenty‐first day of lactation after challenge with endotoxin were detected.Conclusionthe results indicate that administration of LPS and treatment with zinc have effects modulated according to the physiological stage of the female. These effects interfere with the interaction between a mother and her offspring, resulting in short and long term effects in offspring's behavior. Exposure of mothers to bacterial endotoxin modulates the effects caused by zinc and programs the inflammatory responses in the offspring.Support or Funding InformationCoordination for the Improvement of Higher Education Personnel (CAPES)Natural Sciences and Engineering Research Council (NSERC)Canadian Centre for Health and Safety in Agriculture (CCHSA)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Impacts of Selected Fungal Toxins on the Inducement of Agarwood in Gyrinops walla

Agarwood is a resinous wood substance that is produced as a non-specific host response to wounding, insects or microbial invasion by certain trees of family Thymelaeaceae. Most species of Aquilaria and a few species of Gyrinops, Aetoxylon and Gonystylus are capable of producing agarwood. Gyrinops walla is the only agarwood producing tree growing in Sri Lanka which is believed to be endemic. Previous studies have identified that the two fungal species Aspergillus niger and Fusarium soloni are capable of inducing agarwood formation in G. walla. Since those fungi form toxins, it can be assumed that the agarwood production is induced by fungal toxins. Although the ability of fungal species in agarwood production inducement was studied previously, the impact of toxins on agarwood production was never tested. Therefore the present study is aimed to investigate the ability of these mycotoxins to induce the formation of agarwood in G. walla. Secondary metabolites were extracted from one selected isolate of A. niger and F. soloni. The presence of toxins in those metabolites was confirmed through a structured leaf bioassay. Volumes of 5 ml and 10 ml of extracted toxins were inoculated into live healthy G. walla trees and the formation of agarwood resin within the stem was observed using tissue samples collected at 10 cm above and below the inoculation points, 3 months after inoculation. Agarwood resins were extracted from those tissues and resin constituents were analysed by GC-FID method. According to the results, tissue samples obtained from trees inoculated with toxins of F. solani showed higher average resin content (1.69%±0.33) than the trees inoculated with toxins of A. niger (0.81%±0.26) though there was no significant difference (F=2.34, p=0.099). The highest resin percentage was observed with 5 ml inoculation of F. solani toxins (2.00%±0.82). Several resin constituents considered as important markers in identifying agarwood aroma were present in the resins extracted from inoculated trees. Among them, 6-acetyl-7-hydroxy-2,2-dimethyl benzopyran showed the highest abundance. However, the presence of common resin constituents was higher in the inoculation of toxins of A. niger when compared to toxins of F. solani. This study identified that fungal toxins can be used as an effective inoculant to trigger the formation of agarwood in G. walla. However, further research is recommended to verify above observations. Keywords: Agarwood, Gyrinops walla, Fungal toxins, Aspergillus niger, Fusarium solani

Early 1900 s detection of Batrachochytrium dendrobatidis in Korean amphibians.

The pathogenic fungus Batrachochytrium dendrobatidis (Bd) is a major conservation concern because of its role in decimating amphibian populations worldwide. We used quantitative PCR to screen 244 museum specimens from the Korean Peninsula, collected between 1911 and 2004, for the presence of Bd to gain insight into its history in Asia. Three specimens of Rugosa emeljanovi (previously Rana or Glandirana rugosa), collected in 1911 from Wonsan, North Korea, tested positive for Bd. Histology of these positive specimens revealed mild hyperkeratosis – a non-specific host response commonly found in Bd-infected frogs – but no Bd zoospores or zoosporangia. Our results indicate that Bd was present in Korea more than 100 years ago, consistent with hypotheses suggesting that Korean amphibians may be infected by endemic Asian Bd strains.

Infection by Toxoplasma gondii Specifically Induces Host c-Myc and the Genes This Pivotal Transcription Factor Regulates

Toxoplasma gondii infection has previously been described to cause dramatic changes in the host transcriptome by manipulating key regulators, including STATs, NF-κB, and microRNAs. Here, we report that Toxoplasma tachyzoites also mediate rapid and sustained induction of another pivotal regulator of host cell transcription, c-Myc. This induction is seen in cells infected with all three canonical types of Toxoplasma but not the closely related apicomplexan parasite Neospora caninum. Coinfection of cells with both Toxoplasma and Neospora still results in an increase in the level of host c-Myc, showing that c-Myc is actively upregulated by Toxoplasma infection (rather than repressed by Neospora). We further demonstrate that this upregulation may be mediated through c-Jun N-terminal protein kinase (JNK) and is unlikely to be a nonspecific host response, as heat-killed Toxoplasma parasites do not induce this increase and neither do nonviable parasites inside the host cell. Finally, we show that the induced c-Myc is active and that transcripts dependent on its function are upregulated, as predicted. Hence, c-Myc represents an additional way in which Toxoplasma tachyzoites have evolved to specifically alter host cell functions during intracellular growth.

Boosting of nonspecific host response by aromatic spices turmeric and ginger in immunocompromised mice

The present investigation was intended to study the immunostimulant properties of Curcuma longa (turmeric) and Zingiber officinale (ginger) rhizomes on splenic macrophages in carbon tetrachloride intoxicated male albino mice. The study was based on functional parameters like morphology, cell adhesion, phagocytosis, myeloperoxidase release, nitric oxide release and intracellular killing capacity of splenic macrophages. To elucidate the detailed mechanism of boosting of these cell functions, serum levels of TNF-α, and IFN-γ were quantified in different experimental mice groups. Carbon tetrachloride (CCl4) intoxication (0.5ml/kg body weight intraperitoneally) was found to affect the functional status of splenic macrophages as evident from these studies. Moreover, CCl4 intoxicated mice also showed lower levels of cytokines TNF-α and IFN-γ. However, oral administration (singly) of polar fractions of C. longa (50mg/kg b.wt) and Z. officinale (120mg/kg b.wt) rhizomes ameliorated the affects of CCl4, as evident from an increased functional status as well as the serum levels of these cytokines. Based on this study it can be suggested that, polar fractions of C. longa and Z. officinale rhizomes boost the immune system by altering the cytokine milieu of the immunosuppressed macrophages, thus modulating their functional status. Therefore, it can be inferred that dietary intake of C. longa and Z. officinale potentiates the non-specific host defenses against opportunistic infections.

Acute phase protein levels in dogs with mast cell tumours and sarcomas

The acute phase proteins (APP) form part of a non-specific host response to inflammation. They may be induced by a range of different causes, including infection, inflammation, cancer and trauma....

Corynebacterium pseudotuberculosis: Immunological Responses in Animal Models and Zoonotic Potential

Corynebacterium pseudotuberculosis is a member of the Corynebacterium, Mycobacterium and Nocardia (CMN) group that comprises species of medical, veterinary and biotechnological interest. This pathogen mainly affects small ruminants, causing caseous lymphadenitis (CLA), but it also infects bovines, equines, pigs, deer, camels and humans, showing its zoonotic relevance. Phospholipase D (PLD) and the toxic lipid cell wall are the two most wellstudied virulence factors of this bacterium. They are responsible, in part, for the establishment of disease in the host. Current knowledge on the immunity induced by C. pseudotuberculosis indicates that the resistance to infection is a complex process involving components of both the non-specific and specific host responses, in which humoral and cellular immune responses are both operative. Despite this knowledge and the importance of the disease, a satisfactory vaccine model for sheep and goats has not been developed. Moreover, a control program that includes an efficient diagnostic method in addition to vaccination is crucial for avoiding the spread of bacteria inside flocks. Further, because of its zoonotic potential, C. pseudotuberculosis infection of animals can contaminate meat and milk, putting consumers at risk. The ability of C. pseudotuberculosis to infect both animals and humans makes studies on prevention and diagnosis of this pathogen important.

Plasma proteome profiles associated with inflammation, angiogenesis, and cancer.

Tumor development is accompanied by a complex host systemic response, which includes inflammatory and angiogenic reactions. Both tumor-derived and systemic response proteins are detected in plasma from cancer patients. However, given their non-specific nature, systemic response proteins can confound the detection or diagnosis of neoplasia. Here, we have applied an in-depth quantitative proteomic approach to analyze plasma protein changes in mouse models of subacute irritant-driven inflammation, autoreactive inflammation, and matrix associated angiogenesis and compared results to previously described findings from mouse models of polyoma middle T-driven breast cancer and Pdx1-Cre KrasG12D Ink4a/Arf lox/lox -induced pancreatic cancer. Among the confounding models, approximately 1/3 of all quantified plasma proteins exhibited a significant change in abundance compared to control mice. Of the proteins that changed in abundance, the majority were unique to each model. Altered proteins included those involved in acute phase response, inflammation, extracellular matrix remodeling, angiogenesis, and TGFβ signaling. Comparison of changes in plasma proteins between the confounder models and the two cancer models revealed proteins that were restricted to the cancer-bearing mice, reflecting the known biology of these tumors. This approach provides a basis for distinguishing between protein changes in plasma that are cancer-related and those that are part of a non-specific host response.

Immune‐mediated epilepsies

A pathogenic role of immunity in epilepsies has long been suggested based on observations of the efficacy of immune-modulating treatments and, more recently, by the finding of inflammation markers including autoantibodies in individuals with a number of epileptic disorders. Clinical and experimental data suggest that both innate and adaptive immunity may be involved in epilepsy. Innate immunity represents an immediate, nonspecific host response against pathogens via activation of resident brain immune cells and inflammatory mediators. These are hypothesized to contribute to seizures and epileptogenesis. Adaptive immunity employs activation of antigen-specific B and T lymphocytes or antibodies in the context of viral infections and autoimmune disorders. In this article we critically review the evidence for pathogenic roles of adaptive immune responses in several types of epilepsy, and discuss potential mechanisms and therapeutic targets. We highlight future directions for preclinical and clinical research that are required for improved diagnosis and treatment of immune-mediated epilepsies.

Spatiotemporal effects of a controlled-release anti-inflammatory drug on the cellular dynamics of host response

In general, biomaterials induce a non-specific host response when implanted in the body. This reaction has the potential to interfere with the function of the implanted materials. One method for controlling the host response is through local, controlled-release of anti-inflammatory agents. Herein, we investigate the spatial and temporal effects of an anti-inflammatory drug on the cellular dynamics of the innate immune response to subcutaneously implanted poly(lactic-co-glycolic) microparticles. Noninvasive fluorescence imaging was used to investigate the influence of dexamethasone drug loading and release kinetics on the local and systemic inhibition of inflammatory cellular activities. Temporal monitoring of host response showed that inhibition of inflammatory proteases in the early phase was correlated with decreased cellular infiltration in the later phase of the foreign body response. We believe that using controlled-release anti-inflammatory platforms to modulate early cellular dynamics will be useful in reducing the foreign body response to implanted biomaterials and medical devices.

Real-time in vivo detection of biomaterial-induced reactive oxygen species

The non-specific host response to implanted biomaterials is often a key challenge of medical device design. To evaluate biocompatibility, measuring the release of reactive oxygen species (ROS) produced by inflammatory cells in response to biomaterial surfaces is a well-established method. However, the detection of ROS in response to materials implanted in vivo has not yet been demonstrated. Here, we develop a bioluminescence whole animal imaging approach to observe ROS released in response to subcutaneously-implanted materials in live animals. We compared the real-time generation of ROS in response to two representative materials, polystyrene and alginate, over the course of 28 days. High levels of ROS were observed near polystyrene, but not alginate implants, and persisted throughout the course of 28 days. Histological analysis revealed that high levels of ROS correlated not only with the presence of phagocytic cells at early timepoints, but also fibrosis at later timepoints, suggesting that ROS may be involved in both the acute and chronic phase of the foreign body response. These data are the first in vivo demonstration of ROS generation in response to implanted materials, and describe a novel technique to evaluate the host response.

Prophylactic Administration of Bacterially Derived Immunomodulators Improves the Outcome of Influenza Virus Infection in a Murine Model

Prophylactic or therapeutic immunomodulation is an antigen-independent strategy that induces nonspecific immune system activation, thereby enhancing host defense to disease. In this study, we investigated the effect of prophylactic immunomodulation on the outcome of influenza virus infection using three bacterially derived immune-enhancing agents known for promoting distinct immunological profiles. BALB/c mice were treated nasally with either cholera toxin (CT), a mutant form of the CT-related Escherichia coli heat-labile enterotoxin designated LT(R192G), or CpG oligodeoxynucleotide. Mice were subsequently challenged with a lethal dose of influenza A/PR/8/34 virus 24 h after the last immunomodulation treatment and either monitored for survival or sacrificed postchallenge for viral and immunological analysis. Treatment with the three immunomodulators prevented or delayed mortality and weight loss, but only CT and LT(R192G) significantly reduced initial lung viral loads as measured by plaque assay. Analysis performed 4 days postinfection indicated that prophylactic treatments with CT, LT(R192G), or CpG resulted in significantly increased numbers of CD4 T cells, B cells, and dendritic cells and altered costimulatory marker expression in the airways of infected mice, coinciding with reduced expression of pulmonary chemokines and the appearance of inducible bronchus-associated lymphoid tissue-like structures in the lungs. Collectively, these results suggest that, despite different immunomodulatory mechanisms, CT, LT(R192G), and CpG induce an initial inflammatory process and enhance the immune response to primary influenza virus challenge while preventing potentially damaging chemokine expression. These studies provide insight into the immunological parameters and immune modulation strategies that have the potential to enhance the nonspecific host response to influenza virus infection.

Diminished Neural and Cognitive Responses to Facial Expressions of Disgust in Patients with Psoriasis: A Functional Magnetic Resonance Imaging Study

Psoriasis produces significant psychosocial disability; however, little is understood about the neurocognitive mechanisms that mediate the adverse consequences of the social stigma associated with visible skin lesions, such as disgusted facial expressions of others. Both the feeling of disgust and the observation of disgust in others are known to activate the insula cortex. We investigated whether the social impact of psoriasis is associated with altered cognitive processing of disgust using (i) a covert recognition of faces task conducted using functional magnetic resonance imaging (fMRI) and (ii) the facial expression recognition task (FERT), a decision-making task, conducted outside the scanner to assess the ability to recognize overtly different intensities of disgust. Thirteen right-handed male patients with psoriasis and 13 age-matched male controls were included. In the fMRI study, psoriasis patients had significantly (P<0.005) smaller signal responses to disgusted faces in the bilateral insular cortex compared with healthy controls. These data were corroborated by FERT, in that patients were less able than controls to identify all intensities of disgust tested. We hypothesize that patients with psoriasis, in this case male patients, develop a coping mechanism to protect them from stressful emotional responses by blocking the processing of disgusted facial expressions.

Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens

The central nervous system (CNS) regulates innate immune responses through hormonal and neuronal routes. The neuroendocrine stress response and the sympathetic and parasympathetic nervous systems generally inhibit innate immune responses at systemic and regional levels, whereas the peripheral nervous system tends to amplify local innate immune responses. These systems work together to first activate and amplify local inflammatory responses that contain or eliminate invading pathogens, and subsequently to terminate inflammation and restore host homeostasis. Here, I review these regulatory mechanisms and discuss the evidence indicating that the CNS can be considered as integral to acute-phase inflammatory responses to pathogens as the innate immune system.

Innate and adaptive host response during the initial phase of herpes simplex virus encephalitis in the neonatal mouse

To study early events of neonatal herpes simplex virus (HSV) encephalitis and its sequelae, the authors induced a controlled infection in the brains of mice using HSVgH, a genetically modified Disabled Infective Single Cycle virus. Neonatal Balb/C mice were infected with various amounts of HSVgH- virus by intracerebral injection. Results showed that the survival of infected mice was dependent on the amount of virus injected. Infection with 200,000 plaque forming units (pfu) of HSVgH-, virus resulted in 0% survival, whereas 25,000 pfu resulted in 75% survival. If the mice died, 98% of the deaths occurred between 3 and 7 days after infection. Replication competent virus was recovered from 20% of mice brains infected with 25,000 pfu of HSVgH-. Neutralizing antibodies were not detected 6 weeks post infection in sera of mice, which survived infection with 25,000 pfu of HSVgH-. LacZ histochemistry and immunoperoxidase staining using anti-HSV and anti- beta-galactosidase antibodies revealed that the infection was limited to the site of injection. Tissue destruction was observed at the site of inoculation 3 days post infection using cresyl violet staining. At 3 days post infection adjacent sections showed positive cells for viral antigens and apoptotic cells in the infected area. Immunoperoxidase staining using antibodies to surface markers showed microglial activation beginning on day 1 and astrocyte proliferation beginning on day 3 post infection. B and T lymphocytes were not detected on day 1 through 7 post infection. This controlled experimental HSV infection suggests a limited non-specific early host response in the neonate to HSV encephalitis.