Sleep fragmentation disrupts Lyme arthritis resolution in mice.

STUDY OBJECTIVES: Lyme arthritis is a common late-stage complication of infection by Borrelia burgdorferi, the agent of Lyme disease. Patients with Lyme arthritis report increased levels of sleep disturbance associated with pain. Using a mouse model of experimental Lyme arthritis, we investigated the effect of disrupted sleep on the development and resolution of joint inflammation. METHODS: Lyme arthritis-susceptible C3H/HeJ mice (n = 10/group) were infected with B. burgdorferi and were left either alone (control) or subjected to sleep fragmentation (SF). Arthritis development or resolution were monitored. The impact of SF on immune and inflammatory parameters such as arthritis severity scores, anti-borrelia antibody production, and bacterial clearance was measured. We also determined the effect of SF on arthritis resolution in C3H mice deficient in leukotriene (LT) B4 signaling (BLT1/2-/-) who display delayed Lyme arthritis resolution. RESULTS: SF had no significant impact on Lyme arthritis development or inflammatory parameters regardless of whether SF treatment began 1 week prior to or congruent with infection. However, initiation of SF at the peak of arthritis resulted in a significant delay in arthritis resolution as measured by joint edema, arthritis severity scores, and decreased bacterial clearance from the joint. This was accompanied by significant changes in joint cytokine transcription levels (e.g., increased TNFα and decreased IL-4). SF has no significant impact on Lyme arthritis resolution in the BLT1/2-/- mice. CONCLUSIONS: Poor sleep, especially near the peak of arthritis inflammation, may delay initiation of resolution programs possibly through altering cytokine production and host immune responses, leading to defects in spirochete clearance and prolonged disease.

12/15-lipoxygenase activity promotes efficient inflammation resolution in a murine model of Lyme arthritis.

Infection of C3H/HeJ (C3H) mice with Borrelia burgdorferi results in the development of a robust inflammatory arthritis that peaks around 3-4 weeks post-infection and then spontaneously resolves over the next few weeks. Mice lacking cyclooxygenase (COX)-2 or 5-lipoxygenase (5-LO) activity develop arthritis similar to wild-type mice but display delayed or prolonged joint resolution. Since 12/15-lipoxygenase (12/15-LO) activity is generally down-stream of both COX-2 and 5-LO activity and results in the production of pro-resolution lipids such as lipoxins and resolvins among others, we investigated the impact of 12/15-LO deficiency on the resolution of Lyme arthritis in mice on a C3H background. We found the expression of Alox15 (12/15-LO gene) peaked around 4-weeks post-infection in C3H mice suggesting a role for 12/15-LO in mediating arthritis resolution. A deficiency in 12/15-LO resulted in exacerbated ankle swelling and arthritis severity during the resolution phase without compromising anti-Borrelia antibody production and spirochete clearance. However, clearance of inflammatory cells was impeded. Therapeutic treatment of B. burgdorferi-infected C3H mice with lipoxin A4 (LXA4) near the peak of disease resulted in significantly decreased ankle swelling and a switch of joint macrophages to a resolving phenotype but did not directly impact arthritis severity. These results demonstrate that 12/15-LO lipid metabolites are important components of inflammatory arthritis resolution in murine Lyme arthritis and may be a therapeutic target for treatment of joint edema and pain for Lyme arthritis patients without compromising spirochete clearance.

Elevated Temperature Reduces Overwintering Survival of an Avian Ectoparasite, the Swallow Bug (Hemiptera: Cimicidae: Cimex vicarius).

The survival of insects that are dormant in winter may either increase or decrease as a consequence of elevated winter temperatures under climate change. Warming can be deleterious when metabolism of the overwintering life stages increases to the point that energy reserves are exhausted before postoverwintering reemergence. We examined experimentally how overwintering survival of swallow bugs (Hemiptera: Cimicidae: Cimex vicarius Horvath), an ectoparasite primarily of cliff swallows (Passeriformes: Hirundinidae: Petrochelidon pyrrhonota Vieillot), was affected by a 3°C rise in mean daily temperature for populations in Oklahoma, Nebraska, and North Dakota. Adult and nymphal swallow bugs exposed to elevated temperature had an average reduction of approximately 31% in overwintering survival (from July/August to April/May), relative to controls exposed to current region-specific ambient-like conditions. Adult males in both groups survived less well in Nebraska and North Dakota than adult males in Oklahoma, but there was no consistent latitudinal effect of the elevated heat treatment. Our results indicate that projected increases in mean temperature in the Great Plains by 2050 could result in fewer swallow bugs surviving the winter and thus a reduced population size upon the arrival of their primary host in the spring, potentially affecting cliff swallow reproductive success, site use, and breeding phenology. Global climate change may alter the dynamics of host-parasite systems by reducing overall parasite abundance.

Change in beak overhangs of cliff swallows over 40 years: Partly a response to parasites?

Some birds exhibit a maxillary overhang, in which the tip of the upper beak projects beyond the lower mandible and may curve downward. The overhang is thought to help control ectoparasites on the feathers. Little is known about the extent to which the maxillary overhang varies spatially or temporally within populations of the same species. The colonial cliff swallow (Petrochelidon pyrrhonota) has relatively recently shifted to almost exclusive use of artificial structures such as bridges and highway culverts for nesting and consequently has been exposed to higher levels of parasitism than on its ancestral cliff nesting sites. We examined whether increased ectoparasitism may have favored recent changes in the extent of the maxillary overhang. Using a specimen collection of cliff swallows from western Nebraska, USA, spanning 40 years and field data on live birds, we found that the extent of the maxillary overhang increased across years in a nonlinear way, peaking in the late 2000's, and varied inversely with cliff swallow colony size for unknown reasons. The number of fleas on nestling cliff swallows declined in general over this period. Those birds with perceptible overhangs had fewer swallow bugs on the outside of their nest, but they did not have higher nesting success than birds with no overhangs. The intraspecific variation in the maxillary overhang in cliff swallows was partly consistent with it having a functional role in combatting ectoparasites. The temporal increase in the extent of the overhang may be a response by cliff swallows to their relatively recent increased exposure to parasitism. Our results demonstrate that this avian morphological trait can change rapidly over time.

Smaller brained cliff swallows are more likely to die during harsh weather.

The cognitive-buffer hypothesis proposes that more harsh and unpredictable environments favour animals with larger brains and resulting greater cognitive skills. Comparisons across taxa have supported the hypothesis, but it has rarely been tested within a species. We measured brain size, as inferred from head dimensions, for 1141 cliff swallow specimens collected in western Nebraska, 1982-2018. Cliff swallows starving to death during unusual late-spring cold snaps had significantly smaller brains than those dying from other causes, suggesting that brain size in this species can affect foraging success and that greater cognitive ability may confer advantages when conditions exceed normal environmental extremes. Brain size declined significantly with the size of the breeding colony from which a specimen came. Larger brains may be favoured in smaller colonies that represent more unpredictable and more challenging social environments where there is less public information on food sources and less collective vigilance against predators, even in relatively normal conditions. Our results provide intraspecific support for the cognitive-buffer hypothesis and emphasize the potential evolutionary impact of rare climatic events.

Identification and Quantification of Bioactive Molecules Inhibiting Pro-inflammatory Cytokine Production in Spent Coffee Grounds Using Metabolomics Analyses.

In this study, we assessed the anti-inflammatory properties of spent coffee grounds. Methanolic extracts of spent coffee grounds obtained from 3 Arabica cultivars possess compounds that exerted inhibitory effects on the secretion of inflammatory mediators (TNF-α, IL-6, and IL-10) induced by a human pro-monocytic cell line differentiated with PMA and stimulated with lipopolysaccharide (LPS). Our results indicated that the cytokine suppressive activities of the spent coffee ground (SCG) extracts were different among coffee cultivars tested. Hawaiian Kona extracts exhibited inhibitory effects on the expression of 3 examined cytokines, Ethiopian Yirgacheffe extracts reduced the secretion of TNF-α and IL-6, and Costa Rican Tarrazu extracts decreased the secretion of IL-6 only. Untargeted metabolomics analyses of SCG extracts led to the putative identification of 26 metabolites with known anti-inflammatory activities. Multiple metabolites (i.e., chrysin, daidzein, eugenol, naringenin, naringin, oxyresveratrol, pectolinarin, resveratrol, tectochrysin, theaflavin, vanillic acid, and vitexin rhamnoside) identified in the SCGs represent possible novel anti-inflammatory compounds. Of the 26 identified metabolites, the 12 compounds that had high relative intensities in all of the extracts were successfully quantified using liquid chromatography-tandem mass spectrometry analyses. Results from the targeted analyses indicated that caffeine and 5-caffeoylquinic acid (CQA) were the most abundant compounds in the SCG extracts. The contents of caffeine ranged from 0.38 mg/g (Ethiopian Yirgacheffe) - 0.44 mg/g (Costa Rican Tarrazu), whereas 5-CQA concentrations were in the range of 0.24 mg/g (Costa Rican Tarrazu) - 0.34 mg/g (Ethiopian Yirgacheffe). The presence of multiple anti-inflammatory compounds in SCGs provides a promising natural source for cosmetic and pharmaceutical industries.

Elimination of Tobacco rattle virus from viruliferous Paratrichodorus allius in greenhouse pot experiments through cultivation of castle russet.

Corky ringspot (CRS) is a widespread potato tuber necrotic disease caused by Tobacco rattle virus (TRV) infection. In the Pacific Northwest, this virus is transmitted by the stubby root nematode (SRN) within the genus Paratrichodorus. Remediating CRS affected fields is a major challenge that can be mitigated by growing plant varieties that are resistant to TRV infection. Growing alfalfa has been shown to reduce TRV levels in CRS infested fields over time but the development of a potato cultivar with these same capabilities would be of great economic benefit to potato growers. Castle Russet is a new potato clone that does not develop symptoms of CRS disease. To assess its ability to reduce soil virus load, Castle Russet, tobacco var. "Samsun NN", alfalfa var. "Vernema", and Russet Burbank potato were grown for a period of 1 to 3 months in soils containing viruliferous SRN populations at two different inoculation pressures (60 nematodes/pot and 1060 nematodes/pot) in greenhouse pot experiments. SRN population size and the presence of TRV were assessed over several months post inoculation. Results indicate that plant host and length of exposure significantly influence SRN population dynamics, whereas the TRV infection status of bait plants was significantly affected by both of these factors as well as inoculation pressure. These results suggest that both alfalfa var. "Vernema" and Castle Russet are resistant to TRV infection and may potentially be used to eliminate the virus from fields affected by CRS.Corky ringspot (CRS) is a widespread potato tuber necrotic disease caused by Tobacco rattle virus (TRV) infection. In the Pacific Northwest, this virus is transmitted by the stubby root nematode (SRN) within the genus Paratrichodorus. Remediating CRS affected fields is a major challenge that can be mitigated by growing plant varieties that are resistant to TRV infection. Growing alfalfa has been shown to reduce TRV levels in CRS infested fields over time but the development of a potato cultivar with these same capabilities would be of great economic benefit to potato growers. Castle Russet is a new potato clone that does not develop symptoms of CRS disease. To assess its ability to reduce soil virus load, Castle Russet, tobacco var. "Samsun NN", alfalfa var. "Vernema", and Russet Burbank potato were grown for a period of 1 to 3 months in soils containing viruliferous SRN populations at two different inoculation pressures (60 nematodes/pot and 1060 nematodes/pot) in greenhouse pot experiments. SRN population size and the presence of TRV were assessed over several months post inoculation. Results indicate that plant host and length of exposure significantly influence SRN population dynamics, whereas the TRV infection status of bait plants was significantly affected by both of these factors as well as inoculation pressure. These results suggest that both alfalfa var. "Vernema" and Castle Russet are resistant to TRV infection and may potentially be used to eliminate the virus from fields affected by CRS.

Correction to: Transcriptome profiling of resistance response to Meloidogyne chitwoodi introgressed from wild species Solanum bulbocastanum into cultivated potato.

Following the publication of this article [1], the authors noted an error in Figure 11.

Leukotriene B4 receptor BLT1 signaling is critical for neutrophil apoptosis and resolution of experimental Lyme arthritis.

Eicosanoids are powerful mediators of inflammation and are known to drive both the progression and regression of arthritis. We previously reported the infection of C3H 5-lipoxygenase (LO)-deficient mice with Borrelia burgdorferi results in prolonged nonresolving Lyme arthritis. Here we define the role of the 5-LO metabolite leukotriene (LT)B4 and its high-affinity receptor, BLT1, in this response. C3H and C3H BLT1-/- mice were infected with B. burgdorferi and arthritis progression was monitored by ankle swelling over time. Similar to 5-LO-/- mice, BLT1-/- mice developed nonresolving Lyme arthritis characterized by increased neutrophils in the joint at later time points than WT mice, but with fewer apoptotic (caspase-3+ ) neutrophils. In vitro, BLT1-/- neutrophils were defective in their ability to undergo apoptosis due to the lack of LTB4 -mediated down-regulation of cAMP, subsequent failure to induce Death-Inducing Signaling Complex (DISC) components, and decreased FasL and CD36 expression. Inhibition of adenylyl cyclase with SQ 22,536 restored BLT1-/- BMN apoptosis, FasL and CD36 expression, and clearance by macrophages. We conclude that LTB4/BLT1 signaling has an unexpected critical role in mediating neutrophil apoptosis via the down-regulation of cAMP. Loss of BLT1 signaling led to defective clearance of neutrophils from the inflamed joint and failed arthritis resolution.

Variation in neophobia among cliff swallows at different colonies.

Animal groups often represent nonrandom subsets of individuals, and increasing evidence indicates that individuals may sort among groups based on their personalities. The size of a group can predict its personality composition in some species due to differential suitability of a personality for groups of certain sizes, and the group itself may function more effectively if particular personality types are present. We quantified cliff swallow (Petrochelidon pyrrhonota) behavioral measures using linear and generalized linear mixed models to identify whether they: (1) varied among individuals within colonies and among colonies, (2) were related to reproductive success, and (3) predicted levels of parental care. Significant among-individual and among-colony site variation in a cliff swallow's latency to enter its nest when presented with a novel stimulus was revealed. We also found significant among-individual variation in the number of attacks directed toward a novel stimulus at the nest and in the response to broadcast of a cliff swallow alarm call recording, but among site variation in these measures was not significant. We did not find evidence for behavioral syndromes linking the personalities measured. Differences among individuals in latency to enter the nest and the number of attacks were not significantly related to reproductive success or to the extent to which birds fed their nestlings. However, extent of nestling feeding was significantly predicted by the number of mist net captures. The limited evidence in general of systematic variation in the behavior we measured among cliff swallow colonies may reflect the different and sometimes opposing selection pressures on behavior in different social environments. Future work should perhaps examine variation in other behavioral traits, such as foraging, in cliff swallow colonies of different sizes.

Transcriptome profiling of resistance response to Meloidogyne chitwoodi introgressed from wild species Solanum bulbocastanum into cultivated potato.

BACKGROUND: Meloidogyne chitwoodi commonly known as Columbia root-knot nematode or CRKN is one of the most devastating pests of potato in the Pacific Northwest of the United States of America. In addition to the roots, it infects potato tubers causing internal as well as external defects, thereby reducing the market value of the crop. Commercial potato varieties with CRKN resistance are currently unavailable. Race specific resistance to CRKN has been introgressed from the wild, diploid potato species Solanum bulbocastanum into the tetraploid advanced selection PA99N82-4 but there is limited knowledge about the nature of its resistance mechanism. In the present study, we performed histological and differential gene expression profiling to understand the mode of action of introgressed CRKN resistance in PA99N82-4 in comparison to the CRKN susceptible variety Russet Burbank. RESULTS: Histological studies revealed that the nematode juveniles successfully infect both resistant and susceptible root tissue by 48 h post inoculation, but the host resistance response restricts nematode feeding site formation in PA99N82-4. Differential gene expression analysis shows that 1268, 1261, 1102 and 2753 genes were up-regulated in PA99N82-4 at 48 h, 7 days, 14 days and 21 days post inoculation respectively, of which 61 genes were common across all the time points. These genes mapped to plant-pathogen interaction, plant hormonal signaling, antioxidant activity and cell wall re-enforcement pathways annotated for potato. CONCLUSION: The introgressed nematode resistance in PA99N82-4 is in the form of both pattern-triggered immune response and effector-triggered immune response, which is mediated by accumulation of reactive oxygen species and hypersensitive response (HR). Salicylic acid is playing a major role in the HR. Polyamines and suberin (a component of the Casperian strip in roots) also play an important role in mediating the resistance response. The present study provides the first ever comprehensive insights into transcriptional changes among M. chitwoodi resistant and susceptible potato genotypes after nematode inoculation. The knowledge generated in the present study has implications in breeding for CRKN resistance in potato.

Black Walnut (Juglans nigra) Extracts Inhibit Proinflammatory Cytokine Production From Lipopolysaccharide-Stimulated Human Promonocytic Cell Line U-937.

Black walnut (Juglans nigra L.) is an excellent source of health-promoting compounds. Consumption of black walnuts has been linked to many health benefits (e.g., anti-inflammatory) stemming from its phytochemical composition and medicinal properties, but these effects have not been systematically studied or characterized. In this study, potential anti-inflammatory compounds found in kernel extracts of 10 black walnut cultivars were putatively identified using a metabolomic profiling analysis, revealing differences in potential anti-inflammatory capacities among examined cultivars. Five cultivars were examined for activities in the human promonocytic cell line U-937 by evaluating the effects of the extracts on the expression of six human inflammatory cytokines/chemokines using a bead-based, flow cytometric multiplex assay. The methanolic extracts of these cultivars were added at four concentrations (0.1, 0.3, 1, and 10 mg/ml) either before and after the addition of lipopolysaccharide (LPS) to human U-937 cells to examine their effect on cytokine production. Results from cytotoxicity and viability assays revealed that the kernel extracts had no toxic effect on the U-937 cells. Of the 13 cytokines [interleukin (IL)-1ß, tumor necrosis factor alpha (TNF-α), monocyte chemoattractant protein (MCP)-1, IL-6, IL-8, IL-10, IL-12, IL-17, IL-18, IL-23, IL-33, interferon (IFN)-α, IFN-γ] measured, only six were detected under the culture conditions. The production of the six detected cytokines by phorbol 12-myristate 13-acetate (PMA)-differentiated, LPS-stimulated U-937 was significantly inhibited by the kernel extracts from two cultivars Surprise and Sparrow when the extracts were added before the addition of LPS. Other cultivars (Daniel, Mystry, and Sparks) showed weak or no significant effects on cytokine production. In contrast, no inhibitory effect was observed on the production of cytokines by PMA-differentiated, LPS-stimulated U-937 when the kernel extracts were added after the addition of LPS. The findings suggest that the extracts from certain black walnut cultivars, such as Sparrow and Surprise, are promising biological candidates for potentially decreasing the severity of inflammatory disease.

Treatment of Borrelia burgdorferi-Infected Mice with Apoptotic Cells Attenuates Lyme Arthritis via PPAR-γ.

Infection of mice with Borrelia burgdorferi causes an inflammatory arthritis that peaks 3-4 wk postinfection and then spontaneously resolves. Although the recruitment of neutrophils is known to drive the development of arthritis, mechanisms of disease resolution remain unclear. Efficient clearance of apoptotic cells (AC) is likely an important component of arthritis resolution. In this article, we show the number of AC increases in the joints of B. burgdorferi-infected mice around day 21 postinfection and peaks around day 28. Injection of AC directly into the ankles of B. burgdorferi-infected mice limited ankle swelling but had no effect on spirochete clearance or arthritis severity scores. In vitro, addition of AC to bone marrow macrophage cultures decreased B. burgdorferi-induced TNF-α and KC and increased IL-10. In addition, phagocytosis of B. burgdorferi and neutrophil migration to LTB4 were inhibited by AC. Exogenous AC caused an increase in peroxisome proliferator-activated receptor-γ (PPAR-γ) expression both in vitro and in vivo during B. burgdorferi infection. The PPAR-γ agonist rosiglitazone elicited similar changes in macrophage cytokine production and neutrophil migration as exogenous AC. Addition of the PPAR-γ antagonist GW 9662 abrogated the effects of AC in vitro. Injection of rosiglitazone directly into the tibiotarsal joints of B. burgdorferi-infected mice decreased ankle swelling and immune cell recruitment, similar to the injection of AC. These results suggest that clearance of AC plays a role in the resolution of inflammation during experimental Lyme arthritis through the activation of PPAR-γ. PPAR-γ agonists, such as rosiglitazone, may therefore be effective treatments for inducing arthritis resolution.

Ecological correlates of group integrity among dispersing cliff swallows.

Breeding colonies of birds represent groups of individuals that associate during one breeding season, at least partially dissociate for the non-breeding season, and may re-associate the next year through collective settlement at another breeding site. Little is known about the extent to which colonial birds maintain group integrity when occupying different sites in different years or the benefits of long-term associations among colonial individuals. For cliff swallows (Petrochelidon pyrrhonota) in western Nebraska, USA, we examined ecological correlates and potential benefits associated with group integrity. Using a dataset of over 25,000 individuals, we found that associations between dispersing cliff swallows were greater than would be predicted by purely random settlement among colony sites. The extent of group integrity varied widely among sites, with birds seeming to settle together more often at sites with fewer ectoparasites and at colonies similar in size and closer in physical proximity to the one they had previously occupied. Some associations of birds lasted three years in which they used a different site each year. Successful colonies had higher levels of group integrity among their settlers than did colonies that failed completely. Cliff swallows that were known to have settled with at least one conspecific from the previous year's site had a higher survival the next year than those not known to have settled with past residents. The results are consistent with cliff swallows choosing colonies based in part on parasite load and with sorting among colonies based on the birds' preferences for colonies of certain sizes.

Parasites favour intermediate nestling mass and brood size in cliff swallows.

A challenge of life-history theory is to explain why animal body size does not continue to increase, given various advantages of larger size. In birds, body size of nestlings and the number of nestlings produced (brood size) have occasionally been shown to be constrained by higher predation on larger nestlings and those from larger broods. Parasites also are known to have strong effects on life-history traits in birds, but whether parasitism can be a driver for stabilizing selection on nestling body size or brood size is unknown. We studied patterns of first-year survival in cliff swallows (Petrochelidon pyrrhonota) in western Nebraska in relation to brood size and nestling body mass in nests under natural conditions and in those in which hematophagous ectoparasites had been removed by fumigation. Birds from parasitized nests showed highest first-year survival at the most common, intermediate brood-size and nestling-mass categories, but cliff swallows from nonparasitized nests had highest survival at the heaviest nestling masses and no relationship with brood size. A survival analysis suggested stabilizing selection on brood size and nestling mass in the presence (but not in the absence) of parasites. Parasites apparently favour intermediate offspring size and number in cliff swallows and produce the observed distributions of these traits, although the mechanisms are unclear. Our results emphasize the importance of parasites in life-history evolution.

Assessing Potato Cultivar Sensitivity to Tuber Necrosis Caused by Tobacco rattle virus.

Tobacco rattle virus (TRV) causes the economically important corky ring spot disease in potato. Chemical control is difficult due to the soilborne nature of the TRV-transmitting nematode vector, and identifying natural host resistance against TRV is considered to be the optimal control measure. The present study investigated the sensitivity of 63 cultivars representing all market types (evaluated at North Dakota and Washington over 2 years) for the incidence of TRV-induced tuber necrosis and severity. This article also investigates the cultivar-location interaction (using a mixed-effects model) for TRV-induced necrosis. TRV-induced tuber necrosis (P < 0.0001) and severity (P < 0.0001) were significantly different among cultivars evaluated separately in North Dakota and Washington trials. Mixed-effects model results of pooled data (North Dakota and Washington) demonstrated that the interaction of cultivar and location had a significant effect (P = 0.03) on TRV-induced necrosis. Based on the virus-induced tuber necrosis data from both years and locations, cultivars were categorized into sensitive, moderately sensitive, insensitive, and moderately insensitive groups. Based on data from North Dakota, 10 cultivars, including Bintje, Centennial Russet, Ciklamen, Gala, Lelah, Oneida Gold, POR06V12-3, Rio Colorado, Russian Banana, and Superior, were rated as insensitive to TRV-induced tuber necrosis. Similar trials assessing TRV sensitivity among cultivars conducted in Washington resulted in a number of differences in sensitivity rankings compared with North Dakota trials. A substantial shift in sensitivity of some potato cultivars to TRV-induced tuber necrosis was observed between the two locations. Four cultivars (Centennial Russet, Oneida Gold, Russian Banana, and Superior) ranked as insensitive for North Dakota trials were ranked as sensitive for Washington trials. These results can assist the potato industry in making cultivar choices to reduce the economic impact of TRV-induced tuber necrosis.

Borrelia burgdorferi infection induces lipid mediator production during Lyme arthritis.

Experimental Lyme arthritis provides a mouse model for exploring the development of pathology following infection of C3H mice with Borrelia burgdorferi. Infected mice develop a reliable inflammatory arthritis of the ankle joint with severity that typically peaks around two to three weeks post-infection and then undergoes spontaneous resolution. This makes experimental Lyme arthritis an excellent model for investigating the mechanisms that drive both the development and resolution phases of inflammatory disease. Eicosanoids are powerful lipid mediators of inflammation and are known to regulate multiple aspects of inflammatory processes. While much is known about the role of eicosanoids in regulating immune responses during autoimmune disease and cancer, relatively little is known about their role during bacterial infection. In this review, we discuss the role of eicosanoid biosynthetic pathways in mediating inflammatory responses during bacterial infection using experimental Lyme arthritis as a model system. We point out the critical role eicosanoids play in disease development and highlight surprising differences between sterile autoimmune responses and those occurring in response to bacterial infection. These differences should be kept in mind when designing therapies and treatments for inflammatory diseases.

No Detectable Insecticide Resistance in Swallow Bugs (Hemiptera: Cimicidae) Following Long-Term Exposure to Naled (Dibrom 8).

The swallow bug, Oeciacus vicarius Horvath, is a hematophagous ectoparasite of the cliff swallow, Petrochelidon pyrrhonota Vieillot, and is closely related to bed bugs (Cimex spp.). Evolution of insecticide resistance has been documented for bed bugs but not studied in Oeciacus. For periods of 17 and 32 yr, two cliff swallow colonies in western Nebraska were treated during the summer breeding season using the organophosphate insecticide Dibrom. Despite continual treatments, O. vicarius has been observed frequently within these colonies. We evaluated the efficacy of Dibrom 8 on O. vicarius during the 2016 season at two treated colonies and four that had never experienced treatment. Dibrom 8 was found to be effective in 100% of trials, with immobilization within minutes and death within 72 h, for individuals from all colonies. In control treatments (water), individuals collected from treated colonies exhibited greater survival than individuals from untreated colonies, and those from active colonies (bugs fed) had greater survival than those from inactive colonies (bugs unfed). A residual effect was observed in both lab and field trials: 100% mortality occurred in the lab after exposure to filter paper substrates treated both 5 and 10 d earlier, and in the field, nests treated once early in the season had O. vicarius counts 43 d later that were <1% of those from untreated nests within the same colony. We hypothesize that the lack of resistance results from the limited potential for resistance allele fixation due to outbreeding and frequent immigration of insecticide-naïve individuals.

Macrophage LTB4 drives efficient phagocytosis of Borrelia burgdorferi via BLT1 or BLT2.

Unresolved experimental Lyme arthritis in C3H 5-lipoxygenase (5-LOX)-/- mice is associated with impaired macrophage phagocytosis of Borrelia burgdorferi In the present study, we further investigated the effects of the 5-LOX metabolite, leukotriene (LT)B4 on phagocytosis of B. burgdorferi Bone marrow-derived macrophages (BMDMs) from 5-LOX-/- mice were defective in the uptake and killing of B. burgdorferi from the earliest stages of spirochete internalization. BMDMs from mice deficient for the LTB4 high-affinity receptor (BLT1-/-) were also unable to efficiently phagocytose B. burgdorferi Addition of exogenous LTB4 augmented the phagocytic capability of BMDMs from both 5-LOX-/- and BLT1-/- mice, suggesting that the low-affinity LTB4 receptor, BLT2, might be involved. Blocking BLT2 activity with the specific antagonist, LY255283, inhibited phagocytosis in LTB4-stimulated BLT1-/- BMDMs, demonstrating a role for BLT2. However, the lack of a phagocytic defect in BLT2-/- BMDMs suggested that this was a compensatory effect. In contrast, 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid, a natural BLT2-specific high-affinity ligand, and resolvin E1, a BLT1 agonist, were both unable to boost phagocytosis in BMDMs from either 5-LOX-/- or BLT1-/- mice, suggesting a specific role for LTB4 in mediating phagocytosis in murine macrophages. This study demonstrates that LTB4 promotes macrophage phagocytosis of bacteria via BLT1, and that BLT2 can fulfill this role in the absence of BLT1.

Temporal Role for MyD88 in a Model of Brucella-Induced Arthritis and Musculoskeletal Inflammation.

Brucella spp. are facultative intracellular Gram-negative bacteria that cause the zoonotic disease brucellosis, one of the most common global zoonoses. Osteomyelitis, arthritis, and musculoskeletal inflammation are common focal complications of brucellosis in humans; however, wild-type (WT) mice infected systemically with conventional doses of Brucella do not develop these complications. Here we report C57BL/6 WT mice infected via the footpad with 103 to 106 CFU of Brucella spp. display neutrophil and monocyte infiltration of the joint space and surrounding musculoskeletal tissue. Joint inflammation is detectable as early as 1 day postinfection and peaks 1 to 2 weeks later, after which WT mice are able to slowly resolve inflammation. B and T cells were dispensable for the onset of swelling but required for resolution of joint inflammation and infection. At early time points, MyD88-/- mice display decreased joint inflammation, swelling, and proinflammatory cytokine levels relative to WT mice. Subsequently, swelling of MyD88-/- joints surpassed WT joint swelling, and resolution of joint inflammation was prolonged. Joint bacterial loads in MyD88-/- mice were significantly greater than those in WT mice by day 3 postinfection and at all time points thereafter. In addition, MyD88-/- joint inflammatory cytokine levels on day 3 and beyond were similar to WT levels. Collectively these data demonstrate MyD88 signaling mediates early inflammatory responses in the joint but also contributes to subsequent clearance of Brucella and resolution of inflammation. This work also establishes a mouse model for studying Brucella-induced arthritis, musculoskeletal complications, and systemic responses, which will lead to a better understanding of focal complications of brucellosis.