Influenza virus in breast milk

Ferret mother-infantDuring breastfeeding, mothers provide the infant with nutrients, beneficial bacteria, and immune protection. Fluids from the infant may also enter the mammary gland through retrograde flux of the nipple. Studies in a ferret model reveal that influenza virus replicates in the mammary gland, is shed in breast milk and transmitted to the infant. Virus may also travel in the opposite direction, from infant to mother.

The role of the mammary gland in influenza virus transmission was studied using a ferret model comprising lactating mothers and nursing infants. Intranasal inoculation of nursing mother ferrets with the 2009 H1N1 influenza virus lead to viral replication and development of influenza in both mother and infant. When the study design was reversed, and 4 week old nursing ferrets were inoculated intranasally with the same virus, viral replication and disease ensued first in the infants, and then in the mothers. Infectious virus was recovered both in the mammary glands and in the nipples at day 4 post infant inoculation, and in mother’s milk from 3-5 days post infant inoculation. Histopathological examination of sections of mammary glands from infected mothers revealed destruction of the mammary architecture.

These results show that nursing infants may pass influenza virus to mothers. It seems clear that influenza virus replicates in the mammary gland and that infectious virus is present in milk. How does this virus infect the mother? One possibility is that infection is transmitted by respiratory contact with virus-containing milk, or by inhalation of aerosols produced by nursing. How influenza virus in the mammary gland would reach the mother’s lung via the blood to cause respiratory disease is more difficult to envision and seems unlikely.

When influenza virus was inoculated into the mammary gland of lactating mothers via the lactiferous ducts, both mother and breast feeding infant developed serious influenza. Infectious virus was detected first in the nasal wash of infants, then later in the nasal wash of mothers. Breast milk contained infectious virus starting on day 2 after inoculation. Histopathological examination of sections from infected mammary glands revealed destruction of glandular architecture and cessation of milk production. This observation is consistent with the results of gene expression analysis of RNA from virus infected mammary glands, which revealed reduction in transcripts of genes associated with milk production.

To determine if human breast cells can be infected with influenza virus, three different human epithelial breast cell lines were infected with the 2009 H1N1 virus strain. Virus-induced cell killing was observed and infectious virus was produced.

Even if we assume that influenza virus can replicate in the human breast, the implications for influenza transmission and disease severity are not clear. Transmission of HIV-1 from mother to infant by breast milk has been well documented. In contrast to influenza virus, HIV-1 is present in the blood from where it spreads to the breast. Most human influenza virus strains do not enter the blood so it seems unlikely that virus would spread to the breast of a mother infected via the respiratory route. However, viral RNA has been detected in the blood of humans infected with the 2009 H1N1 strain, the virus used in these ferret studies. Therefore we cannot rule out the possibility that some strains of influenza virus spread from lung via the blood to the breast, allowing infection of a nursing infant. Some answers might be provided by determining if influenza virus can be detected in the breast milk of humans with influenza.

What would be the implication of a nursing infant infecting the mother’s breast with influenza virus? As I mentioned above, it seems unlikely that this virus would enter the blood, and even if it could, how would the virus infect the apical side of the respiratory epithelium? What does seem clear is that viral replication in the breast could lead to a decrease in milk production which could be detrimental to the infant. If the mother had multiple births, then influenza virus might be transmitted to siblings nursing on the infected mother.

Are you wondering how an infant drinking influenza virus-laded breast milk acquires a respiratory infection? Recently it has been shown that influenza virus replicates in the soft palate of ferrets. The soft palate has mucosal surfaces that face both the oral cavity and the nasopharynx. Ingested virus could first replicate in the soft palate, then spread to the nasopharynx and the lung. A simpler explanation is that nursing produces virus-containing aerosols which are inhaled by the infant.

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Origin of segmented RNA virus genomes

influenza virusSegmented genomes abound in the RNA virus world. They are found in virus particles from different families, and can be double stranded (Reoviridae) or single stranded of (+) (Closteroviridae) or (-) (Orthomyxoviridae) polarity. Our recent discussion of the advantages of a segmented viral genome, compared with monopartitie genomesgenerated a good discussion. Another interesting question concerns the evolutionary relationship between the two genome types. Did monopartite viral genomes emerge first, then later fragmented to form segmented genomes? Some recent experiments provide insight into this question.

Insight into how a monopartite RNA genome might have fragmented to form a segmented genome comes from studies with the picornavirus foot-and-mouth disease virus (FMDV). The genome of this virus is a single molecule of (+) RNA. Serial passage of the virus in baby hamster kidney cells led to the emergence of genomes with two different large deletions (417 and 999 bases) in the coding region. Each mutant genome is not infectious, but when introduced together into cells, infectious virus is produced. This virus stock consists of a mixture of the two mutant genomes packaged separately into virus particles. Infection takes place because of complementation: each genome provides the proteins missing in the other.

Further study of the deleted FMDV genomes revealed the presence of point mutations in other regions of the genome. These mutations had accumulated before the deletions appeared, and increased the fitness of the deleted genome compared with the wild type genome.

These results illuminate the first steps in fragmentation of monopartite viral RNA, possibly a pathway to a segmented genome. It is very interesting that the point mutations that gave the fragmented RNAs a fitness advantage over the standard RNA arose before fragmentation occurred – further evidence that mutations occur in a specific sequence. As the authors write:

Thus, exploration of sequence space by a viral genome (in this case an unsegmented RNA) can reach a point of the space in which a totally different genome structure (in this case, a segmented RNA) is favored over the form that performed the exploration.

While the fragmentation of the FMDV genome may represent a step on the path to segmentation, its relevance to what occurs in nature is unclear, because the results were obtained in cell culture.

A compelling picture of the genesis of a segmented RNA genome comes from the discovery of a new tick borne virus in China, Jingmen tick virus (JMTV). The genome of this virus comprises four segments of (+) stranded RNA. Two of the RNA segments have no known sequence homologs, while the other two are related to sequences of flaviviruses. The RNA genome of flaviviruses is not segmented: it is a single strand of (+) sense RNA. The proteins encoded by RNA segments 1 and 3 of JMTV are non-structural proteins which are clearly related to the flavivirus NS5 and NS3 proteins.

The genome structure of JMTV suggests that at some point in the past a flavivirus genome fragmented to produce the RNA segments encoding the NS3 and NS5-like proteins. This fragmentation might have initially taken place as shown for FMDV in cell culture, by fixing of deletion mutations that complemented one another. Next, co-infection of this segmented flavivirus with another unidentified virus took place to produce the precursor of JMTV.

Both sets of findings were accidents, made while investigating unrelated problems. The results provide new clues about the origins of segmented RNA viruses, and are examples of the value and unpredictable nature of basic science research.