An Overview of Management Considerations for Mongolian Gerbils (Meriones unguiculatus), Cats (Felis catus), and Dogs (Canis familiaris) as Hosts for Brugia Infection.

Lymphatic filariasis is a mosquito-borne parasitic infection affecting an estimated 51.4 million people. Brugia malayi and Brugia pahangi are used in research because common nonprimate research species such as Mongolian gerbils (Meriones unguiculatus), cats (Felis catus), and dogs (Canis familiaris) can maintain the life cycle of these species of filarial nematodes. Although overall care and management of animals infected with Brugia spp. is relatively straightforward, there are some unique challenges and special considerations that must be addressed when managing a research colony infected with these parasites. In this review, we discuss our experience, share insight into biosafety and clinical management, and describe the expected clinical signs associated with Brugia infection in gerbils, cats, and dogs.

Functional partitioning of sentence processing and emotional prosody in the right perisylvian cortex after perinatal stroke.

In healthy adults different language abilities-sentence processing versus emotional prosody-are supported by the left (LH) versus the right hemisphere (RH), respectively. However, after LH stroke in infancy, RH regions support both abilities with normal outcomes. We investigated how these abilities co-exist in RH regions after LH perinatal stroke by evaluating the overlap in the activation between two fMRI tasks that probed auditory sentence processing and emotional prosody processing. We compared the overlap for these two functions in the RH of individuals with perinatal stroke with the symmetry of these functions in the LH and RH of their healthy siblings. We found less activation overlap in the RH of individuals with LH perinatal stroke than would be expected if both functions retained their typical spatial layout, suggesting that their spatial segregation may be an important feature of a functioning language system.

One right can make a left: sentence processing in the right hemisphere after perinatal stroke.

When brain regions that are critical for a cognitive function in adulthood are irreversibly damaged at birth, what patterns of plasticity support the successful development of that function in an alternative location? Here we investigate the consistency of language organization in the right hemisphere (RH) after a left hemisphere (LH) perinatal stroke. We analyzed fMRI data collected during an auditory sentence comprehension task on 14 people with large cortical LH perinatal arterial ischemic strokes (left hemisphere perinatal stroke (LHPS) participants) and 11 healthy sibling controls using a "top voxel" approach that allowed us to compare the same number of active voxels across each participant and in each hemisphere for controls. We found (1) LHPS participants consistently recruited the same RH areas that were a mirror-image of typical LH areas, and (2) the RH areas recruited in LHPS participants aligned better with the strongly activated LH areas of the typically developed brains of control participants (when flipped images were compared) than the weakly activated RH areas. Our findings suggest that the successful development of language processing in the RH after a LH perinatal stroke may in part depend on recruiting an arrangement of frontotemporal areas reflective of the typical dominant LH.

Interactions between B cells and T follicular regulatory cells enhance susceptibility to Brucella infection independent of the anti-Brucella humoral response.

Brucellosis, caused by facultative, intracellular Brucella spp., often results in chronic and/or lifelong infection. Therefore, Brucella must employ mechanisms to subvert adaptive immunity to cause chronic infection. B lymphocytes enhance susceptibility to infection with Brucella spp. though the mechanisms remain unclear. Here we investigated the role of antibody secretion, B cell receptor (BCR) specificity, and B cell antigen presentation on susceptibility to B. melitensis. We report that mice unable to secrete antibody do not display altered resistance to Brucella. However, animals with B cells that are unable to recognize Brucella through their BCR are resistant to infection. In addition, B cell MHCII expression enhances susceptibility to infection in a CD4+ T cell-dependent manner, and we found that follicular B cells are sufficient to inhibit CD4+ T cell-mediated immunity against Brucella. B cells promote development of T follicular helper (TFH) and T follicular regulatory (TFR) cells during Brucella infection. Inhibition of B cell and CD4+ T cell interaction via CD40L blockade enhances resistance to Brucella in a B cell dependent manner concomitant with suppression of TFH and TFR differentiation. Conversely, PD-1 blockade increases Brucella burdens in a B and CD4+ T cell dependent manner while augmenting T regulatory (TReg) and TFR responses. Intriguingly, TFR deficiency enhances resistance to Brucella via a B cell dependent, but antibody independent mechanism. Collectively, these results demonstrate B cells support TFR responses that promote susceptibility to Brucella infection independent of the antibody response.

Fifteen research needs for understanding climate change impacts on ecosystems and society in the Norwegian High North.

There is an urgent need to understand and address the risks associated with a warming climate for ecosystems and societies in the Arctic and sub-Arctic regions. There are major gaps in our understanding of the complex effects of climate change-including extreme events, cascading impacts across ecosystems, and the underlying socioecological dynamics and feedbacks-all of which need collaborative efforts to be resolved. Here, we present results where climate scientists, ecologists, social scientists, and practitioners were asked to identify the most urgent research needs for understanding climate change impacts and to identify the actions for reducing future risks in catchment areas in the Norwegian High North, a region that encompasses both Arctic and sub-Arctic climates in northern Norway. From a list of 77 questions, our panel of 19 scientists and practitioners identified 15 research needs that should be urgently addressed. We particularly urge researchers to investigate cross-ecosystem impacts and the socioecological feedbacks that could amplify or reduce risks for society.

Innate Lymphoid Cells and Interferons Limit Neurologic and Articular Complications of Brucellosis.

Brucellosis is a globally significant zoonotic disease. Human patients with brucellosis develop recurrent fever and focal complications, including arthritis and neurobrucellosis. The current study investigated the role of innate lymphoid cells (ILCs) in the pathogenesis of focal brucellosis caused by Brucella melitensis. After footpad infection, natural killer cells and ILC1 cells both limited joint colonization by Brucella. Mice lacking natural killer cells, and in particular mice lacking all ILCs, also developed marked arthritis after footpad infection. Following pulmonary infection, mice lacking adaptive immune cells and ILCs developed arthritis, neurologic complications, and meningitis. Adaptive immune cells and ILCs both limited colonization of the brain by Brucella following pulmonary infection. Transcriptional analysis of Brucella-infected brains revealed marked up-regulation of genes associated with inflammation and interferon responses, as well as down-regulation of genes associated with neurologic function. Type II interferon deficiency resulted in colonization of the brain by Brucella, but mice lacking both type I and type II interferon signaling more rapidly developed clinical signs of neurobrucellosis, exhibited hippocampal neuronal loss, and had higher levels of Brucella in their brains than mice lacking type II interferon signaling alone. Collectively, these findings indicate ILCs and interferons play an important role in prevention of focal complications during Brucella infection, and that mice with deficiencies in ILCs or interferons can be used to study pathogenesis of neurobrucellosis.

Beach litter sources around Nuuk, Greenland: An analysis by UArctic summer school graduate course students.

Modeling studies illustrate the potential for long-range transport of plastics into the Arctic, although the degree to which this occurs remains relatively undocumented. We utilised a teaching exercise at a UArctic summer school graduate course in Nuuk, Greenland to conduct a preliminary in-depth analysis of beach litter sources in the Nuup Kangerlua fjord. Students and instructors collected and analysed 1800 litter items weighing 200 kg from one location in the fjord and another at its mouth. The results suggest a predominance of local sources to macrolitter, rather than long-range transport from Europe. Fisheries-related items and rope were common. Packaging which could be identified was largely suspected to be products distributed in Greenland, and soft plastics, which rarely disperse far from its source, were also common. The results suggest local measures to reduce mismanaged waste and emissions from fisheries are important for reducing marine litter in West Greenland.

Language and developmental plasticity after perinatal stroke.

The mature human brain is lateralized for language, with the left hemisphere (LH) primarily responsible for sentence processing and the right hemisphere (RH) primarily responsible for processing suprasegmental aspects of language such as vocal emotion. However, it has long been hypothesized that in early life there is plasticity for language, allowing young children to acquire language in other cortical regions when LH areas are damaged. If true, what are the constraints on functional reorganization? Which areas of the brain can acquire language, and what happens to the functions these regions ordinarily perform? We address these questions by examining long-term outcomes in adolescents and young adults who, as infants, had a perinatal arterial ischemic stroke to the LH areas ordinarily subserving sentence processing. We compared them with their healthy age-matched siblings. All participants were tested on a battery of behavioral and functional imaging tasks. While stroke participants were impaired in some nonlinguistic cognitive abilities, their processing of sentences and of vocal emotion was normal and equal to that of their healthy siblings. In almost all, these abilities have both developed in the healthy RH. Our results provide insights into the remarkable ability of the young brain to reorganize language. Reorganization is highly constrained, with sentence processing almost always in the RH frontotemporal regions homotopic to their location in the healthy brain. This activation is somewhat segregated from RH emotion processing, suggesting that the two functions perform best when each has its own neural territory.

Nucleotide receptors mediate protection against neonatal sepsis and meningitis caused by alpha-hemolysin expressing Escherichia coli K1.

Neonatal meningitis-associated Escherichia coli (NMEC) is among the leading causes of bacterial meningitis and sepsis in newborn infants. Several virulence factors have been identified as common among NMEC, and have been shown to play an important role in the development of bacteremia and/or meningitis. However, there is significant variability in virulence factor expression between NMEC isolates, and relatively little research has been done to assess the impact of variable virulence factor expression on immune cell activation and the outcome of infection. Here, we investigated the role of NMEC strain-dependent P2X receptor (P2XR) signaling on the outcome of infection in neonatal mice. We found that alpha-hemolysin (HlyA)-expressing NMEC (HlyA+ ) induced robust P2XR-dependent macrophage cell death in vitro, while HlyA- NMEC did not. P2XR-dependent cell death was inflammasome independent, suggesting an uncoupling of P2XR and inflammasome activation in the context of NMEC infection. In vivo inhibition of P2XRs was associated with increased mortality in neonatal mice infected with HlyA+ NMEC, but had no effect on the survival of neonatal mice infected with HlyA- NMEC. Furthermore, we found that P2XR-dependent protection against HlyA+ NMEC in vivo required macrophages, but not neutrophils or NLRP3. Taken together, these data suggest that HlyA+ NMEC activates P2XRs which in turn confers macrophage-dependent protection against infection in neonates. In addition, our findings indicate that strain-dependent virulence factor expression should be taken into account when studying the immune response to NMEC.

Developmental changes in neural lateralization for visual-spatial function: Evidence from a line-bisection task.

Studies of hemispheric specialization have traditionally cast the left hemisphere as specialized for language and the right hemisphere for spatial function. Much of the supporting evidence for this separation of function comes from studies of healthy adults and those who have sustained lesions to the right or left hemisphere. However, we know little about the developmental origins of lateralization. Recent evidence suggests that the young brain represents language bilaterally, with 4-6-year-olds activating the left-hemisphere regions known to support language in adults as well as homotopic regions in the right hemisphere. This bilateral pattern changes over development, converging on left-hemispheric activation in late childhood. In the present study, we ask whether this same developmental trajectory is observed in a spatial task that is strongly right-lateralized in adults-the line bisection (or "Landmark") task. We examined fMRI activation among children ages 5-11 years as they were asked to judge which end of a bisected vertical line was longer. We found that young children showed bilateral activation, with activation in the same areas of the right hemisphere as has been shown among adults, as well as in the left hemisphere homotopic regions. By age 10, activation was right-lateralized. This strongly resembles the developmental trajectory for language, moving from bilateral to lateralized activation. We discuss potential underlying mechanisms and suggest that understanding the development of lateralization for a range of cognitive functions can play a crucial role in understanding general principles of how and why the brain comes to lateralize certain functions.

MyD88-Dependent Glucose Restriction and Itaconate Production Control Brucella Infection.

Brucellosis is one of the most common global zoonoses and is caused by facultative intracellular bacteria of the genus Brucella. Numerous studies have found that MyD88 signaling contributes to protection against Brucella; however, the underlying mechanism has not been entirely defined. Here, we show that MyD88 signaling in hematopoietic cells contributes both to inflammation and to control of Brucella melitensis infection in vivo. While the protective role of MyD88 in Brucella infection has often been attributed to promotion of gamma interferon (IFN-γ) production, we found that MyD88 signaling restricts host colonization by B. melitensis even in the absence of IFN-γ. In vitro, we show that MyD88 promotes macrophage glycolysis in response to B. melitensis. Interestingly, a B. melitensis mutant lacking the glucose transporter, GluP, was more highly attenuated in MyD88-/- than in wild-type mice, suggesting MyD88 deficiency results in an increased availability of glucose in vivo, which Brucella can exploit via GluP. Metabolite profiling of macrophages identified several metabolites regulated by MyD88 in response to B. melitensis, including itaconate. Subsequently, we found that itaconate has antibacterial effects against Brucella and also regulates the production of proinflammatory cytokines in B. melitensis-infected macrophages. Mice lacking the ability to produce itaconate were also more susceptible to B. melitensis in vivo. Collectively, our findings indicate that MyD88-dependent changes in host metabolism contribute to control of Brucella infection.

Nitric oxide inhibits interleukin-1-mediated protection against Escherichia coli K1-induced sepsis and meningitis in a neonatal murine model.

Neonatal meningitis-associated Escherichia coli (NMEC) is a leading cause of sepsis and meningitis in newborn infants. Neonates are known to have impaired inflammasome activation and interleukin (IL)-1 production. However, it is unknown what role this plays in the context of NMEC infection. Here we investigated the role of IL-1 signaling in the pathogenesis of NMEC infection. We found both IL-1ß and IL-1α were secreted from macrophages and microglial cells in response to NMEC in a Toll-like receptor 4- and NLR family pyrin domain containing 3 (NPLR3)-dependent manner. Intracerebral infection of adult mice indicated a protective role of IL-1 signaling during NMEC infection. However, IL-1 receptor blockade in wild-type neonatal mice did not significantly alter bacterial loads in the blood or brain, and we, therefore, investigated whether protection conferred by IL-1 was age dependent. Neonates are known to have increased nitric oxide (NO) levels compared with adults, and we found NO inhibited the secretion of IL-1 by macrophages in response to NMEC. In contrast to our results in wild-type neonates, blockade of IL-1 receptor in neonates lacking inducible nitric oxide synthase (iNOS) led to significantly increased bacterial loads in the blood and brain. These data indicate IL-1 signaling is protective during NMEC infection in neonates only when iNOS is absent. Collectively, our findings suggest that increased NO production by neonates inhibits IL-1 production, and that this suppresses the protective role of IL-1 signaling in response to NMEC infection. This may indicate a general mechanism for increased susceptibility of neonates to infection and could lead to new therapeutic strategies in the future.

Development of bilateral parietal activation for complex visual-spatial function: Evidence from a visual-spatial construction task.

The neural representation of visual-spatial functions has traditionally been ascribed to the right hemisphere, but little is known about these representations in children, including whether and how lateralization of function changes over the course of development. Some studies suggest bilateral activation early in life that develops toward right-lateralization in adulthood, while others find evidence of right-hemispheric dominance in both children and adults. We used a complex visual-spatial construction task to examine the nature of lateralization and its developmental time course in children ages 5-11 years. Participants were shown two puzzle pieces and were asked whether the pieces could fit together to make a square; responses required either mental translation of the pieces (Translation condition) or both mental translation and rotation of the pieces (Rotation condition). Both conditions were compared to a matched Luminance control condition that was similar in terms of visual content and difficulty but required no spatial analysis. Group and single-subject analyses revealed that the Rotation and Translation conditions elicited strongly bilateral activation in the same parietal and occipital locations as have been previously found for adults. These findings show that visual-spatial construction consistently elicits robust bilateral activation from age 5 through adulthood. This challenges the idea that spatial functions are all right-lateralized, either during early development or in adulthood. More generally, these findings provide insights into the developmental course of lateralization across different spatial skills and how this may be influenced by the computational requirements of the particular functions involved.

The neural basis of language development: Changes in lateralization over age.

We have long known that language is lateralized to the left hemisphere (LH) in most neurologically healthy adults. In contrast, findings on lateralization of function during development are more complex. As in adults, anatomical, electrophysiological, and neuroimaging studies in infants and children indicate LH lateralization for language. However, in very young children, lesions to either hemisphere are equally likely to result in language deficits, suggesting that language is distributed symmetrically early in life. We address this apparent contradiction by examining patterns of functional MRI (fMRI) language activation in children (ages 4 through 13) and adults (ages 18 through 29). In contrast to previous studies, we focus not on lateralization per se but rather on patterns of left-hemisphere (LH) and right-hemisphere (RH) activation across individual participants over age. Our analyses show significant activation not only in the LH language network but also in their RH homologs in all of the youngest children (ages 4 through 6). The proportion of participants showing significant RH activation decreases over age, with over 60% of adults lacking any significant RH activation. A whole-brain correlation analysis revealed an age-related decrease in language activation only in the RH homolog of Broca's area. This correlation was independent of task difficulty. We conclude that, while language is left-lateralized throughout life, the RH contribution to language processing is also strong early in life and decreases through childhood. Importantly, this early RH language activation may represent a developmental mechanism for recovery following early LH injury.

B Cells Inhibit CD4+ T Cell-Mediated Immunity to Brucella Infection in a Major Histocompatibility Complex Class II-Dependent Manner.

Brucella spp. are facultative intracellular bacteria notorious for their ability to induce a chronic, and often lifelong, infection known as brucellosis. To date, no licensed vaccine exists for prevention of human disease, and mechanisms underlying chronic illness and immune evasion remain elusive. We and others have observed that B cell-deficient mice challenged with Brucella display reduced bacterial burden following infection, but the underlying mechanism has not been clearly defined. Here, we show that at 1 month postinfection, B cell deficiency alone enhanced resistance to splenic infection ∼100-fold; however, combined B and T cell deficiency did not impact bacterial burden, indicating that B cells only enhance susceptibility to infection when T cells are present. Therefore, we investigated whether B cells inhibit T cell-mediated protection against Brucella Using B and T cell-deficient Rag1-/- animals as recipients, we demonstrate that adoptive transfer of CD4+ T cells alone confers marked protection against Brucella melitensis that is abrogated by cotransfer of B cells. Interestingly, depletion of CD4+ T cells from B cell-deficient, but not wild-type, mice enhanced susceptibility to infection, further confirming that CD4+ T cell-mediated immunity against Brucella is inhibited by B cells. In addition, we found that the ability of B cells to suppress CD4+ T cell-mediated immunity and modulate CD4+ T cell effector responses during infection was major histocompatibility complex class II (MHCII)-dependent. Collectively, these findings indicate that B cells modulate CD4+ T cell function through an MHCII-dependent mechanism which enhances susceptibility to Brucella infection.

What you say versus how you say it: Comparing sentence comprehension and emotional prosody processing using fMRI.

While language processing is often described as lateralized to the left hemisphere (LH), the processing of emotion carried by vocal intonation is typically attributed to the right hemisphere (RH) and more specifically, to areas mirroring the LH language areas. However, the evidence base for this hypothesis is inconsistent, with some studies supporting right-lateralization but others favoring bilateral involvement in emotional prosody processing. Here we compared fMRI activations for an emotional prosody task with those for a sentence comprehension task in 20 neurologically healthy adults, quantifying lateralization using a lateralization index. We observed right-lateralized frontotemporal activations for emotional prosody that roughly mirrored the left-lateralized activations for sentence comprehension. In addition, emotional prosody also evoked bilateral activation in pars orbitalis (BA47), amygdala, and anterior insula. These findings are consistent with the idea that analysis of the auditory speech signal is split between the hemispheres, possibly according to their preferred temporal resolution, with the left preferentially encoding phonetic and the right encoding prosodic information. Once processed, emotional prosody information is fed to domain-general emotion processing areas and integrated with semantic information, resulting in additional bilateral activations.

Major Histocompatibility Complex Class II-Restricted, CD4+ T Cell-Dependent and -Independent Mechanisms Are Required for Vaccine-Induced Protective Immunity against Coxiella burnetii.

To understand the role of major histocompatibility complex class I (MHC-I) and MHC-II in vaccine-mediated protection against Coxiella burnetii, we evaluated the protective efficacy of a formalin-inactivated C. burnetii Nine Mile phase I vaccine (PIV) in ß2-microglobulin-deficient (B2m KO) and MHC-II-deficient (MHC-II KO) mice. Vaccination reduced disease severity in wild-type (WT) and B2m KO mice but failed to reduce bacterial burden in MHC-II KO mice. This suggests that the MHC-II antigen presentation pathway is required for PIV-mediated protection against C. burnetii infection. MHC-I and MHC-II affect antibody isotype switching, since both PIV-vaccinated B2m KO and MHC-II KO mice produced less Coxiella-specific IgG than PIV-vaccinated WT mice. Interestingly, MHC-II and CD4 deficiencies were not equivalent in terms of splenomegaly and bacterial clearance. This demonstrates a partial role for CD4+ T cells while revealing MHC-II-restricted, CD4-independent mechanisms. Adoptive transfer of CD4+ T cells from PIV-vaccinated WT mice to naive CD4-deficient (CD4 KO) mice demonstrated that antigen-experienced CD4+ T cells are sufficient to generate protection. Conversely, transfer of naive CD4+ T cells to PIV-vaccinated CD4 KO mice exacerbates disease. Using Tbet-deficient (Tbet KO) mice, we showed a partial role for Th1 subset CD4+ T cells in vaccine protection. Furthermore, Th1-independent roles for Tbet were suggested by significant differences in disease between PIV-vaccinated Tbet KO and CD4 KO mice. Interferon gamma was shown to contribute to the host inflammatory response but not bacterial clearance. Collectively, these findings suggest that vaccine-induced protective immunity against a murine model of experimental Q fever requires MHC-II-restricted, CD4+ T cell-dependent and -independent mechanisms that can be exploited for a new-generation human Q fever vaccine.

Eosinophils Affect Antibody Isotype Switching and May Partially Contribute to Early Vaccine-Induced Immunity against Coxiella burnetii.

Coxiella burnetii is an obligate intracellular Gram-negative bacterium which causes human Q fever. An acidified citrate cysteine medium (ACCM-2) has been developed which mimics the intracellular replicative niche of C. burnetii and allows axenic growth of the bacteria. To determine if C. burnetii cultured in ACCM-2 retains immunogenicity, we compared the protective efficacies of formalin-inactivated C. burnetii Nine Mile phase I (PIV) and phase II (PIIV) vaccines derived from axenic culture 7, 14, and 28 days postvaccination. PIV conferred significant protection against virulent C. burnetii as early as 7 days postvaccination, which suggests that ACCM-2-derived PIV retains immunogenicity and protectivity. We analyzed the cellular immune response in spleens from PIV- and PIIV-vaccinated mice by flow cytometry at 7 and 14 days postvaccination and found significantly more granulocytes in PIV-vaccinated mice than in PIIV-vaccinated mice. Interestingly, we found these infiltrating granulocytes to be SSChigh CD11b+ CD125+ Siglec-F+ (where SSChigh indicates a high side scatter phenotype) eosinophils. There was no change in the number of eosinophils in PIV-vaccinated CD4-deficient mice compared to the level in controls, which suggests that eosinophil accumulation is CD4+ T cell dependent. To evaluate the importance of eosinophils in PIV-mediated protection, we vaccinated and challenged eosinophil-deficient ΔdblGATA mice. ΔdblGATA mice had significantly worse disease than their wild-type counterparts when challenged 7 days postvaccination, while no significant difference was seen at 28 days postvaccination. Nevertheless, ΔdblGATA mice had elevated serum IgM with decreased IgG1 and IgG2a whether mice were challenged at 7 or 28 days postvaccination. These results suggest that eosinophils may play a role in early vaccine protection against C. burnetii and contribute to antibody isotype switching.

Revisiting the Landmark Task as a tool for studying hemispheric specialization: What's really right?

The "Landmark Task" (LT) is a line bisection judgment task that predominantly activates right parietal cortex. The typical version requires observers to judge bisections for horizontal lines that cross their egocentric midline and therefore may depend on spatial attention as well as spatial representation of the line segments. To ask whether the LT is indeed right-lateralized regardless of spatial attention (for which the right hemisphere is known to be important), we examined LT activation in 26 neurologically healthy young adults using vertical (instead of horizontal) stimuli, as compared with a luminance control task that made similar demands on spatial attention. We also varied task difficulty, which is known to affect lateralization in both spatial and language tasks. Despite these changes to the task, we observed right-lateralized parietal activations similar to those reported in other LT studies, both at group level and in individual lateralization indices. We conclude that LT activation is robustly right-lateralized, perhaps uniquely so among commonly-studied spatial tasks. We speculate that the unique properties of the LT reside in its requirement to judge relative magnitudes of the two line segments, rather than in the more general aspects of spatial attention or visual-spatial representation.

IFN-γ-dependent nitric oxide suppresses Brucella-induced arthritis by inhibition of inflammasome activation.

Brucellosis, caused by the intracellular bacterial pathogen Brucella, is a globally important zoonotic disease for which arthritis is the most common focal complication in humans. Wild-type mice infected systemically with Brucella typically do not exhibit arthritis, but mice lacking IFN-γ develop arthritis regardless of the route of Brucella infection. Here, we investigated mechanisms by which IFN-γ suppresses Brucella-induced arthritis. Several cell types, including innate lymphoid cells, contributed to IFN-γ production and suppression of joint swelling. IFN-γ deficiency resulted in elevated joint IL-1ß levels, and severe joint inflammation that was entirely inflammasome dependent, and in particular, reliant on the NLRP3 inflammasome. IFN-γ was vital for induction of the nitric oxide producing enzyme, iNOS, in infected joints, and nitric oxide directly inhibited IL-1ß production and inflammasome activation in Brucella-infected macrophages in vitro. During in vivo infection, iNOS deficiency resulted in an increase in IL-1ß and inflammation in Brucella-infected joints. Collectively, this data indicate that IFN-γ prevents arthritis both by limiting Brucella infection, and by inhibiting excessive inflammasome activation through the induction of nitric oxide.